Methods and devices for non-invasive cerebral and systemic cooling

ABSTRACT

A method for cerebral and systemic cooling by providing a nebulized liquid having a boiling point of 38-300° C. The nebulized liquid is delivered as a mist or a spray via the nasal and/or oral cavities of a patient. The mist causes cooling by direct heat transfer through the nasopharynx and hematogenous cooling through the carotids and the Circle of Willis. Compositions and medical devices for cerebral and systemic cooling are also provided. Cooling assemblies, and methods of use, are also provided that include flexible balloon assemblies that are inserted to various locations in a patient&#39;s body. The flexible balloons are then infused with a liquid having a temperature between about −20° C. and about 37° C. The flexible balloon assemblies can be inserted into the nasal cavity, oral cavity, throat, stomach, and other locations to effect cerebral cooling.

This is a continuation of U.S. application Ser. No. 11/432,285, filedMay 10, 2006, which claims the benefit of the following provisionalapplications: U.S. provisional patent application Ser. No. 60/681,068,entitled “Methods and Devices for Non-Invasive Cerebral and SystemicCooling,” filed May 13, 2005; U.S. provisional patent application Ser.No. 60/717,590, entitled “Methods and Devices for Non-Invasive Cerebraland Systemic Cooling,” filed Sep. 16, 2005; and U.S. provisional patentapplication Ser. No. 60/737,025, entitled “Methods and Devices forNon-Invasive Cerebral and Systemic Cooling,” filed Nov. 15, 2005, all ofwhich are expressly incorporated herein by reference in their entiretyfor all purposes.

FIELD OF THE INVENTION

The invention relates to cerebral and systemic cooling via the nasalcavity, oral cavity, and other parts of the body, and more particularlyto methods and devices for cerebral and systemic cooling using liquidsor liquid mists with boiling points above body temperature and fordelivering liquid mists to the nasopharyngeal cavity.

BACKGROUND OF THE INVENTION

Patients experiencing cerebral ischemia often suffer from disabilitiesranging from transient neurological deficit to irreversible damage(stroke) or death. Cerebral ischemia, i.e., reduction or cessation ofblood flow to the central nervous system, can be characterized as eitherglobal or focal. Global cerebral ischemia refers to reduction of bloodflow within the cerebral vasculature resulting from systemic circulatoryfailure caused by, e.g., shock, cardiac failure, or cardiac arrest.Within minutes of circulatory failure, tissues become ischemic,particularly in the heart and brain.

The most common form of shock is cardiogenic shock, which results fromsevere depression of cardiac performance. The most frequent cause ofcardiogenic shock is myocardial infarction with loss of substantialmuscle mass. Pump failure can also result from acute myocarditis or fromdepression of myocardial contractility following cardiac arrest orprolonged cardiopulmonary bypass. Mechanical abnormalities, such assevere valvular stenosis, massive aortic or mitral regurgitation,acutely acquired ventricular septal defects, can also cause cardiogenicshock by reducing cardiac output. Additional causes of cardiogenic shockinclude cardiac arrhythmia, such as ventricular fibrillation. Withsudden cessation of blood flow to the brain, complete loss ofconsciousness is a sine qua non in cardiac arrest. Cardiac arrest oftenprogresses to death within minutes if active interventions, e.g.,cardiopulmonary resuscitation (CPR), defibrillation, use of inotropicagents and vasoconstrictors such as dopamine, dobutamine, orepinephrine, are not undertaken promptly. The most common cause of deathduring hospitalization after resuscitated cardiac arrests is related tothe severity of ischemic injury to the central nervous system, e.g.,anoxic encephalopathy. The ability to resuscitate patients of cardiacarrest is related to the time from onset to institution of resuscitativeefforts, the mechanism, and the clinical status of the patient prior tothe arrest.

Focal cerebral ischemia refers to cessation or reduction of blood flowwithin the cerebral vasculature resulting in stroke, a syndromecharacterized by the acute onset of a neurological deficit that persistsfor at least 24 hours, reflecting focal involvement of the centralnervous system. Approximately 80% of the stroke population ishemispheric ischemic strokes, caused by occluded vessels that deprivethe brain of oxygen-carrying blood. Ischemic strokes are often caused byemboli or pieces of thrombotic tissue that have dislodged from otherbody sites or from the cerebral vessels themselves to occlude in thenarrow cerebral arteries more distally. Hemorrhagic stroke accounts forthe remaining 20% of the annual stroke population. Hemorrhagic strokeoften occurs due to rupture of an aneurysm or arteriovenous malformationbleeding into the brain tissue, resulting in cerebral infarction. Othercauses of focal cerebral ischemia include vasospasm due to subarachnoidhemorrhage from head trauma or iatrogenic intervention.

Current treatment for acute stroke and head injury is mainly supportive.A thrombolytic agent, e.g., tissue plasminogen activator (t-PA), can beadministered to non-hemorrhagic stroke patients. Treatment with systemict-PA is associated with increased risk of intracerebral hemorrhage andother hemorrhagic complications. Aside from the administration ofthrombolytic agents and heparin, there are no therapeutic optionscurrently on the market for patients suffering from occlusion focalcerebral ischemia. Vasospasm may be partially responsive to vasodilatingagents. The newly developing field of neurovascular surgery, whichinvolves placing minimally invasive devices within the carotid arteriesto physically remove the offending lesion, may provide a therapeuticoption for these patients in the future, although this kind ofmanipulation may lead to vasospasm itself.

In both stroke and cardiogenic shock, patients develop neurologicaldeficits due to reduction in cerebral blood flow. Thus treatments shouldinclude measures to maintain viability of neural tissue, therebyincreasing the length of time available for interventional treatment andminimizing brain damage while waiting for resolution of the ischemia.New devices and methods are thus needed to minimize neurologic deficitsin treating patients with either stroke or cardiogenic shock caused byreduced cerebral perfusion.

Research has shown that cooling the brain may prevent the damage causedby reduced cerebral perfusion. Initially research focused on selectivecerebral cooling via external cooling methods. Studies have also beenperformed that suggest that the cooling of the upper airway can directlyinfluence human brain temperature, see for example Direct cooling of thehuman brain by heat loss from the upper respiratory tract, Zenon Mariak,et al. 8750-7587 The American Physiological Society 1999, incorporatedby reference herein in its entirety. Furthermore, because the distancebetween the roof of the nose and the floor of the anterior cranial fossais usually only a fraction of a millimeter, the nasal cavity might be asite where respiratory evaporative heat loss or convection cansignificantly affect adjacent brain temperatures, especially becausemost of the warming of inhaled air occurs in the uppermost segment ofthe airways. Thus, it would be advantageous to develop a device andmethod for achieving cerebral cooling via the nasal and/or oral cavitiesof a patient.

SUMMARY OF THE INVENTION

The invention relates to methods, devices, and compositions for cerebralcooling, preferably via the nasal and/or oral cavities. The coolingoccurs by direct heat transfer through the nasopharynx as well as byhematogenous cooling through the carotids as they pass by the oropharynxand through the Circle of Willis, which lies millimeters away from thepharynx. The direct cooling will be obtained through evaporative heatloss of a nebulized liquid in the nasal cavity, oral cavity, and/orthroat. Additionally, cooling may occur through convection in the nasalcavity. Such cerebral cooling may help to minimize neurologic deficitsin treating patients with either stroke or cardiogenic shock caused byreduced cerebral perfusion or in the treatment of migraines. In thefollowing description, where a cooling assembly, device, or method isdescribed for insertion into a nostril of a patient, a second coolingassembly or device can optionally also be inserted into the othernostril to maximize cooling.

In one embodiment, the invention provides a method for cerebral cooling.An elongate member can be inserted into a nasal cavity of a patientthrough the patient's nostril. The elongate member may have a proximalend, a distal end, a first lumen extending therebetween, and a pluralityof ports in fluid communication with the first lumen. A perfluorocarbonspray and a gas is then delivered onto a surface of the patient's nasalcavity through the plurality of ports in the elongate member. Theevaporation of the perfluorocarbon from the nasal cavity, which isenhanced by the gas, results in reduction of the cerebral temperature ofthe patient by at least 1° C. in one hour. Alternatively, the cerebraltemperature may be reduced by at least 2° C., alternatively at least 3°C., alternatively at least 4° C., alternatively at least 5° C.,alternatively at least 6° C., alternatively at least 7° C.,alternatively at least 8° C., alternatively at least 9° C.,alternatively at least 10° C. The elongate member may further comprise asecond lumen extending between the proximal and distal ends. The methodmay further include the steps of infusing the perfluorocarbon into thefirst lumen, infusing the gas into the second lumen, and combining theperfluorocarbon and gas at the plurality of ports to form aperfluorocarbon spray. The gas may be oxygen. Additionally, theperfluorocarbon may have a boiling point above 37° C., alternativelybetween about 0° C. and about 160° C., alternatively between about 25°C. and about 140° C. The spray may be directed towards the roof of thenasal cavity and onto the turbinates. Additionally, water or one or moredrugs may also be delivered with the perfluorocarbon spray. The deliveryof water may reduce the drying of the nasal tissues.

In another embodiment, the invention provides an elongate member capableof delivering a nebulized liquid spray to a patient's nasal cavity. Theelongate member has a proximal end, a distal end, and a lumen extendingtherebetween. An outer wall of the elongate member has a plurality ofports that are in fluid communication with the lumen. The plurality ofports may be spaced apart axially and longitudinally along the length ofthe elongate tubular member such that nebulized spray from the portswill substantially cover the whole nasal cavity. The elongate tubularmember may comprise a first lumen extending between the proximal anddistal ends for transporting the liquid. The elongate tubular member mayalso comprise a second lumen extending between the proximal and distalends for transporting a compressed gas.

In use, the elongate member is inserted into a nasal cavity of a patientthrough one of the patient's nostrils and positioned in the nasalcavity. The elongate member may be positioned in the upper nasopharynxsuch that the nebulized spray will be delivered over the nasal plexusand the carotids. The proximal end of the elongate member is placed influid communication with a liquid source. The liquid is nebulized and anebulized liquid spray is delivered into the patient's nasal cavitythrough the plurality of ports. In one embodiment, the liquid isnebulized at each of the plurality of ports on the elongate tubularmember. The liquid and compressed gas may be separately transported tothe ports via the first and second lumens of the elongate tubular memberand only combined at the ports. The volume of liquid delivered may rangefrom about 0.1 to about 20 liters, alternatively about 1 to about 20liters, alternatively about 1 to about 15 liters, alternatively about 1to about 10 liters, alternatively about 1 to about 8 liters,alternatively about 2 to about 6 liters. Unevaporated liquid may also besuctioned or otherwise removed from the patient's nasal pharynx. Acooling helmet may also be used to help lower the cerebral temperatureof the patient. Furthermore, a warming blanket may be used to maintainthe systemic temperature of the patient, or prevent the systemictemperature from decreasing as much as t eh cerebral temperature. Avasodilator may also be delivered to the patient's nasal cavity toenhance vascular cooling capacity. Additionally or alternatively, ahumidifier, such as isotonic saline or water, may also be delivered intothe patient's nasal cavity. Additional air or oxygen may be delivered tothe patient to enhance the evaporative process through a mask placedover the nose of the patient, such as a CPAP nasal mask.

The patient's cerebral, systemic, and nasal temperatures may also bemonitored during this method. The nebulized spray may be delivered at aflow rate sufficient to achieve a gradient of not greater than about0.5° C. between the outer surface of the brain and the inner core of thebrain. The nebulized spray may also be delivered at a flow ratesufficient to achieve a gradient of at least about 1.0° C. between thecerebral temperature and the systemic temperature. The nebulized spraymay also be delivered at a flow rate sufficient to achieve cerebralcooling at a rate greater than about 1.0° C. in hour. The nebulizedspray may also be delivered at a flow rate sufficient to achieve atemperature in the nasal cavity of about 4.0° C. or less.

In an alternative embodiment according to this invention, a nasalcatheter may be used to deliver a spray of liquid to the nasal cavity ofa patient. The nasal catheter may be placed in the nares of thepatient's nose and may be angled to direct the spray outlet at thedesired structures of the nose, for example, the nasal conchae. Inaddition, the distal end of the nasal catheter and may be designed tocause the spray to spread in a pattern which will allow the gas andliquid mixture to contact as much of the desired tissue as possible.Spreading the spray will also minimize the potential of medical traumathat could result form a high velocity stream of liquid directed at thetissue of the nasal cavity. In addition, the distal end of the cathetermay be ‘tipped’, i.e., sealed of in a rounded fashion to provide asmooth surface to avoid damaging the sensitive nasal tissues.

A number of methods for spreading the spray pattern are contemplated.For example, the spray pattern may be formed by creating one or moreholes along opposite sides of the catheter tip, which would create abroad, flat spray perpendicular to the axis of the catheter. Thispattern may be further altered by changing the size, location and numberof holes in the catheter. In addition, this pattern may further includea hole in the tip of the catheter to produce some additional flow in theaxial direction. An alternative spray pattern may be formed by making aslit in the tip of the catheter to produce a fan shaped spray centeredon the axial direction of the catheter. This pattern maybe furtheraltered by varying the width of the slit and the length the slit extendsdown the sides of the catheter. In addition, multiple, intersectingslits may be made in the catheter tip. Another alternative spray patternmay be formed by making a straight or curved cut along opposite sides ofthe catheter wall. The skived cut may extend from and include a portionof the tip. This configuration will produce a wide ‘fan’ shaped spraycovering a broad angle from the perpendicular to the axial direction ofthe catheter. In addition, any of the above described patterns could becombined to create additional spray patterns for the nasal catheter.

In an alternative embodiment, the invention provides a cooling assemblyfor insertion into a nasal cavity of a patient through a patient'snostril. The cooling assembly includes a flexible balloon defining achamber, a first elongate tubular member having a lumen in fluidcommunication with the chamber, and a second elongate tubular memberhaving a lumen in fluid communication with the chamber. The coolingassembly may further comprise a third elongate tubular member having alumen extending from a proximal end to a distal end, wherein theflexible balloon is mounted circumferentially about the third elongatetubular member.

In use, the cooling assembly is inserted into a nasal cavity of apatient through the patient's nostril. A liquid having a temperaturebetween about −20° C. and about 37° C. is infused through the lumen ofthe first elongate tubular member into the chamber of the flexibleballoon. The liquid is then withdrawn, suctioned, or drained from thechamber through the lumen of the second tubular member. During thisprocess, the chamber of the flexible balloon expands to place theflexible balloon in contact with the nasal cavity. The method mayfurther include the step of recirculating the liquid by infusing theliquid through the lumen of the first elongate tubular member andwithdrawing the liquid through the lumen of the second elongate tubularmember. The liquid may be infused using a pump at a flow rate of betweenabout 5 ml/min and about 5 L/min, alternatively between about 100 ml/minand about 1 L/min, alternatively between about 200 ml/min and about 800ml/min, alternatively between about 300 ml/min and about 700 ml/mm,alternatively between about 400 ml/min and about 600 ml/min,alternatively between about 450 ml/min and about 550 ml/min,alternatively about 500 ml/min. Where the cooling assembly comprises aflexible balloon mounted circumferentially about a third elongatetubular member having a lumen, the third elongate tubular member shouldbe positioned such that the lumen is in fluid communication with thepatient's nasopharynx, oropharynx, larynx, and/or esophagus, such thatthe patient can breathe through the lumen of the third elongate tubularmember. Alternatively, a medical device could be passed through thelumen of the third elongate tubular member. A drug may also be elutedfrom a surface of the flexible balloon.

In an alternative embodiment, the invention provides a cooling assemblyfor insertion into a nasal cavity of a patient through a patient'snostril. The cooling assembly includes a first balloon defining achamber and having a port and a second balloon defining a chamber insideof the chamber of the first balloon. A first elongate tubular member hasa lumen in fluid communication with the chamber of the second balloonand a second elongate tubular member also has a lumen in fluidcommunication with the chamber of the second balloon.

In use, the cooling assembly is inserted into a patient's nostril. Thechamber of the first balloon is filled with a first liquid through theport to place the balloon in contact with the nasal cavity. A secondliquid having a temperature between about −5° C. and about 5° C. is theninfused through the lumen of the first elongate tubular member into thechamber of the second balloon. The second liquid exits the chamber ofthe second balloon through the lumen of the second elongate tubularmember. The second liquid also reduces the temperature of the firstliquid, such that a cerebral temperature of the patient is reduced by atleast 1° C. in about one hour. A second cooling assembly could beinserted into the patient's other nostril to maximize cerebral cooling.The first liquid could be water or saline. The second liquid could be aPFC, anti-freeze solution, or a combination thereof.

In an alternative embodiment, the invention provides an alternativecooling assembly for insertion into a nasal cavity of a patient througha patient's nostril. The cooling assembly includes a balloon defining achamber and having a first port with a gas-venting filter and a secondport. A first elongate tubular member has a lumen in fluid communicationwith the chamber of the balloon.

In use, the cooling assembly is inserted into a patient's nostril. Thechamber of the balloon is filled with a first liquid through the secondport to place the balloon in contact with the nasal cavity. A secondliquid having a temperature between about −5° C. and about 5° C. is theninfused through the lumen of the first elongate tubular member into thefirst liquid in the chamber. After contact with the first liquid, thesecond liquid undergoes a phase transition to gas, and the gas is ventedthrough the gas-venting filter. The second liquid also reduces thetemperature of the first liquid, such that a cerebral temperature of thepatient is reduced by at least 1° C. in about one hour. A second coolingassembly could be inserted into the patient's other nostril to maximizecerebral cooling. The first liquid could be water or saline. The secondliquid could be a fluorocarbon having a boiling point below about 37°C., such as Freon or other refrigerant.

In an alternative embodiment, the invention provides a cooling assemblyfor insertion into a nasal cavity of a patient through a patient'snostril. The cooling assembly includes a balloon defining a chamber. Abranched tubular member comprises a first tubular member that branchesinto a second and a third tubular member, all of which have lumens. Thelumen of the first tubular member is in fluid communication with thechamber and with the lumens of the second and third tubular members. Apump is connected to the second tubular member. A cooler is connected tothe pump and to the third tubular member.

In use, the cooling assembly is inserted into a patient's nostril. Thechamber of the balloon is infused with a liquid having a temperaturebetween about −20° C. and about 37° C. through the lumens of the thirdand first tubular members. The liquid is then withdrawn from the chamberthrough the lumens of the first and second tubular members. The chamberof the balloon expands to place the surface of the balloon in contactwith the nasal cavity when the chamber is infused with liquid, such thata cerebral temperature of the patient is reduced by at least 1° C. inabout one hour. A second cooling assembly could be inserted into thepatient's other nostril to maximize cerebral cooling. The liquid can becontinuously recirculated through the chamber of the balloon using apump or other means. The liquid could be water, saline, PFC, anti-freezesolution, or a combination thereof.

In an alternative embodiment, the invention provides a cooling assemblyfor insertion into a nasal cavity of a patient through a patient'snostril. The cooling assembly includes a first elongate tubular member,a flexible balloon, and a second elongate tubular member. The firstelongate tubular member, e.g., a nasogastric tube, has a proximal end, adistal end, a lumen therebetween, and a port at the distal end in fluidcommunication with the lumen. The flexible balloon is mountedcircumferentially about the first elongate tubular member to the distalend, wherein the flexible balloon defines a chamber that is in fluidcommunication with the port and lumen of the first elongate tubularmember. The second elongate tubular member has a proximal end, a distalend, and a lumen therebetween, wherein the lumen is in fluidcommunication with the chamber of the flexible balloon. The flexibleballoon is sized such that, upon expansion, it will substantially fillthe adjacent anatomy. For instance, the distal end of the flexibleballoon is sized such that it can substantially fill the stomach uponexpansion. Alternatively, a second flexible balloon having a chamber influid communication with the first flexible balloon and the port andlumen of the first elongate tubular member may be attached at the distalend of the flexible balloon. This second flexible balloon may be sizedto substantially fill the patient's stomach upon expansion.

In use, the cooling assembly is inserted into a patient through apatient's nostril. The first elongate tubular member is advanced downthe patient's throat, through the patient's esophagus, and into thepatient's stomach. A liquid having a temperature between about −20° C.and about 37° C. is infused through the lumen of the first elongatetubular member into the chamber of the flexible balloon. The liquid isthen withdrawn, drained, or suctioned from the chamber through the lumenof the second elongate tubular member. During this process, the chamberof the flexible balloon expands to place the flexible balloon in contactwith the adjacent anatomy. The method may further include the step ofrecirculating the liquid by infusing the liquid through the lumen of thefirst elongate tubular member and withdrawing the liquid through thelumen of the second elongate tubular member. The liquid may be infusedusing a pump at a flow rate of between about 5 ml/min and about 5 L/min,alternatively between about 100 ml/min and about 1 L/min, alternativelybetween about 200 ml/min and about 800 ml/min, alternatively betweenabout 300 ml/min and about 700 ml/min, alternatively between about 400ml/min and about 600 ml/min, alternatively between about 450 ml/min andabout 550 ml/min, alternatively about 500 ml/min. A drug may also beeluted from a surface of the flexible balloon.

In an alternative embodiment, the invention provides a modifiedlaryngeal mask cooling assembly for insertion into a patient's throat.The cooling assembly includes a first elongate tubular member, aflexible toroidal balloon, and a second elongate tubular member. Thefirst elongate tubular member has a proximal end, a distal end, a lumentherebetween, and a port at the distal end in fluid communication withthe lumen. The flexible toroidal balloon defines a chamber and ismounted at the distal end of the elongate tubular member. The secondelongate tubular member has a proximal end, a distal end, and a lumentherebetween in fluid communication with the chamber of the flexibletoroidal balloon. The third elongate tubular member has a proximal end,a distal end, and a lumen therebetween in fluid communication with thechamber of the flexible toroidal balloon. The assembly may also includea second flexible balloon located on the distal end of the firstelongate tubular member, opposite of the flexible toroidal balloon.

In use, the cooling assembly is inserted into a patient's throat andpositioned such that the flexible toroidal balloon is located over thelarynx. A liquid having a temperature between about −20° C. and about37° C. is infused through the lumen of the second elongate tubularmember into the chamber of the flexible toroidal balloon. The liquid isthen withdrawn, drained, or suctioned from the chamber through the lumenof the third elongate tubular member. During this process, the chamberof the flexible toroidal balloon expands to place the flexible balloonin contact with the adjacent anatomy, i.e., the epiglotis. The methodmay further include the step of recirculating the liquid by infusing theliquid through the lumen of the second elongate tubular member andwithdrawing the liquid through the lumen of the third elongate tubularmember. The liquid may be infused using a pump at a flow rate of betweenabout 5 ml/min and about 5 L/min, alternatively between about 100 ml/minand about 400 ml/min, alternatively between about 150 ml/min and about200 ml/min. A drug may also be eluted from a surface of the flexibletoroidal balloon. Where the cooling system comprises a second flexibleballoon, the second flexible balloon will also be infused with theliquid, either through the lumens of the second and third elongatemembers or through lumens of a fourth and a fifth elongate tubularmember.

In an alternative embodiment, the invention provides a cooling assemblyfor insertion into a patient's oral cavity. The cooling assemblyincludes a flexible balloon or pad, a first tubular member, and a secondtubular member. The flexible balloon or pad defines a chamber. The firsttubular member has a proximal end, a distal end, a lumen therebetween,and a port in fluid communication with the lumen of the first tubularmember and the chamber of the flexible balloon. The second tubularmember has a proximal end, a distal end, a lumen therebetween, and aport in fluid communication with the lumen of the second tubular memberand the chamber of the flexible balloon.

In use, the cooling assembly is inserted into a patient's mouth andpositioned such that the flexible balloon or pad covers theretromandibular area or the peritonsillar region. A liquid having atemperature between about −20° C. and about 37° C. is infused throughthe lumen of the first tubular member into the chamber of the flexibleballoon. The liquid is then withdrawn, drained, or suctioned from thechamber through the lumen of the second tubular member. During thisprocess, the chamber of the flexible balloon or pad expands to place theflexible balloon in contact with the adjacent anatomy, i.e., theretromandibular area or the peritonsillar region. The method may furtherinclude the step of recirculating the liquid by infusing the liquidthrough the lumen of the first tubular member and withdrawing the liquidthrough the lumen of the second tubular member. The liquid may beinfused using a pump at a flow rate of between about 5 ml/min and about5 L/min, alternatively between about 100 ml/min and about 400 ml/min,alternatively between about 150 ml/min and about 200 ml/min. A drug mayalso be eluted from a surface of the flexible balloon.

In another embodiment, the invention provides a gas and liquid deliverysystem. The delivery system includes a flow meter for delivering a gas,a mixing manifold in fluid communication with the flow meter, and areservoir containing a liquid portion and a gas portion. The gas portionof the reservoir is in fluid communication with the flow meter and themixing manifold and the liquid portion independently communicates withthe mixing manifold. The system may further comprise a flow restrictorthat regulates a flow of liquid from the reservoir to the mixingmanifold. The liquid may be a perfluorocarbon such as perfluorohexane or2-methyl-perfluoropentane. The gas being delivered may be oxygen, air,or a combination thereof.

In an alternative embodiment, the invention provides a gas and liquiddelivery system with the following characteristics. The delivery systemincludes a flow meter for delivering a gas, a mixing manifold incommunication with the flow meter through a lumen of a first elongatetubular member, and a sealed reservoir containing a fluid. A lumen of asecond elongate tubular member is in communication with the interior ofthe sealed reservoir and also with the lumen of the first elongatetubular member. The fluid from the sealed reservoir is in communicationwith the mixing manifold through a third elongate tubular member. Thedelivery system may further include a flow restrictor coupled to thethird elongate tubular member capable of regulating a flow rate of fluidfrom the reservoir to the mixing manifold. The liquid may be aperfluorocarbon such as perfluorohexane or 2-methyl perfluoropentane.The gas being delivered may be oxygen, air, or a combination thereof.

In use, the delivery systems described above deliver gas from the flowmeter to the mixing manifold and to the gas portion of the reservoir.Liquid is delivered from the liquid portion of the reservoir to themixing manifold as a result of pressure from the gas building within thegas portion of the reservoir, thereby displacing liquid from the liquidportion of the reservoir into the mixing manifold. The method mayfurther include the step of regulating a flow of the liquid from theliquid portion of the reservoir to the mixing manifold with a flowrestrictor. The liquid and gas in the mixing manifold can then bedelivered into a nasal cavity of a patient through a port in a catheter.

In an alternative embodiment of this invention, thin impermeablemembranes surrounding a space may be placed over the carotid arteriesexternally. For example, the membranes may extend from clavicle to theear lobe and be approximately 4 cm in width. The membranes may be cooledusing a liquid perfluorocarbon, preferably with a boiling point lessthan 37° C., delivered cold or at room temperature. The membrane must befilled such that vapor can still escape. The membranes may be of aradiator shape to increase surface area. In addition, the membranes mayhave an inlet and a larger bore outlet. Adhesive may be used to stickthe membranes to the neck, e.g., like an EKG patch. Alternatively, acollar with cold patches confined to the carotid region may be used. Theliquid in the membranes may be cold saline, refrigerants, orperfluorocarbons with a boiling point of above or below 37° C.Additionally, a vasodilator cream may be applied behind the coolingmembrane to dilate vessels maximally.

In an alternative embodiment of this invention, a thin impermeablemembrane may be placed inside the oral cavity over each carotid behindthe tonsils with adhesive. The membrane may be for example, 4 cm lengthand 1.5 cm width. These membranes may cool in the same way as describedabove. The membrane may be of a radiator shape to increase surface area.In addition, the membranes may have an inlet and a larger bore outlet.The liquid in the membranes may be cold saline, refrigerants, orperfluorocarbons with a boiling point of above or below 37° C. Themembrane should be sized sufficiently small so as not to obstruct theairway or induce gagging as it expands with vapors.

In another alternative embodiment, nasal prongs and/or mouthpiece may beused to circulate cold perfluorocarbon gas, for example, SF6 jet,perfluoropropane or butane, about 1 or 2 degrees in about one hour, torapidly cool the nasopharynx. The patient could be hyperventilated at 12L/min, 6 L gas, 6 L oxygen mixture for a few minutes or longer with theaddition of CO₂ or dead space. This embodiment may be combined with anexternal carotid pad, as previously described, or with a cooling helmetfor additional cerebral cooling.

In another embodiment according to this invention, a nasal catheter isused to deliver a mist or spray of a nebulized liquid into the nasalcavity of a patient. In a preferred embodiment, the catheter may be amulti lumen tube inserted through the nose containing a plurality oflumens. A first lumen is dedicated to spraying liquid and/or oxygen intothe nasal cavities. This may have specialized features for creatingsmall droplets. In an alternative embodiment, the catheter may have aspray nozzle secured to the distal end of the catheter and the spray ormist may be delivered into the nasal cavity via a spray nozzle forfanning or swirling the spray or mist. A second suction tube may beinserted through a second lumen in the catheter and positioned in theesophagus of the patient for suctioning out any vapors of the nebulizedliquid that enter the esophagus. The suction tube may have has slits oropenings along its length for communicating with the lumen of theesophagus and may be on intermittent or continuous suction for removingthe vapors. The geometry allows ‘flow through’ cooling as the liquid isintroduced in the nose and then suctioned out of the upper esophagus.Some of this liquid will evaporate and be exhaled as vapor. This phasechange will draw significant energy from the body. Indirect cooling willbe also obtained as some of the liquid evaporates in the spray plume,chilling the inhaled gas. In an alternative embodiment, the liquid maybe pre-cooled to further facilitate cerebral cooling.

In an alternative embodiment, a specialized nasal catheter is describedfor the application of a nebulized liquid, preferably a perfluorocarbon(PFC), for cerebral and systemic cooling. This embodiment comprises amulti-lumen elongate member with a length operable to extend a patient'sesophagus to be inserted through the nose, and into the esophagus. Aninflatable external balloon is located near the distal end, which may beused to occlude the esophagus. A first lumen of the elongate member maythen be used for suctioning vapor and or liquid from the stomach. Asecond lumen may be exposed proximal to balloon, to allow suctioningvapor or liquid that enters the upper esophagus. In operation, thecatheter is placed and the balloons inflated to occlude the respectivepassages. Gastric suction can be applied per clinical practice. Air (oroxygen) is introduced to the patient through the spray lumen in thenose. A PFC liquid is added to the spray lumen; this will produce a fogof droplets in the nasal cavity. Much of the PFC liquid will impact andcoalesce on the walls of the nasal cavity and associated passages. Thisliquid will then drain down to the throat, the majority of which willenter the esophagus where it can be suctioned through the proximalsuction port and reused. Some may enter the lungs either directly asliquid or as droplets carried on the inhaled breath. In addition, a plugor balloon may be located at the entrance to the nasal cavity to preventany retrograde flow out of the nose. In an alternate embodiment, theelongate member may be bifurcated outside the nose, with an additionalprong and balloon for the other nostril.

In an alternative embodiment according to this invention, a nasalcatheter may be used to deliver a spray of liquid to the nasal cavity ofa patient. The nasal catheter may be placed in the nares of thepatient's nose and may be angled to direct the spray outlet at thedesired structures of the nose, for example, the nasal conchae. Inaddition, the distal end of the nasal catheter and may be designed tocause the spray to spread in a pattern which will allow the gas andliquid mixture to contact as much of the desired tissue as possible.Spreading the spray will also minimize the potential of medical traumathat could result form a high velocity stream of liquid directed at thetissue of the nasal cavity. In addition, the distal end of the cathetermay be ‘tipped’, i.e., sealed of in a rounded fashion to provide asmooth surface to avoid damaging the sensitive nasal tissues.

A number of methods for spreading the spray pattern are contemplated.For example, the spray pattern may be formed by creating one or moreholes along opposite sides of the catheter tip, which would create abroad, flat spray perpendicular to the axis of the catheter. Thispattern may be further altered by changing the size, location and numberof holes in the catheter. In addition, this pattern may further includea hole in the tip of the catheter to produce some additional flow in theaxial direction. An alternative spray pattern may be formed by making aslit in the tip of the catheter to produce a fan shaped spray centeredon the axial direction of the catheter. This pattern maybe furtheraltered by varying the width of the slit and the length the slit extendsdown the sides of the catheter. In addition, multiple, intersectingslits may be made in the catheter tip. Another alternative spray patternmay be formed by making a straight or curved cut along opposite sides ofthe catheter wall. The skyved cut may extend from and include a portionof the tip. This configuration will produce a wide ‘fan’ shaped spraycovering a broad angle from the perpendicular to the axial direction ofthe catheter. In addition, any of the above described patterns could becombined to create additional spray patterns for the nasal catheter.

In an alternative embodiment, the proximal end of the nasal catheter maybe designed to further include one or more expandable members mounted onthe distal end. In use, the nasal catheter may be inserted into one ofthe patient's nostrils and positioned in the posterior aspect of thenasal cavity, proximal to the opening to the nasopharynx. Oncepositioned in posterior aspect of the nasal cavity, the expandablemember may be expanded to conform to the posterior aspect of the nasalcavity and form a seal isolating the nasal cavity from the nasopharynxand the rest of the patient's airways in order to prevent non-vaporizedliquid from leaking into the pharynx. Once isolated, the spray of liquidmay be delivered into one of the patient's nostrils and circulatedthough the nasal cavity to allow for rapid cooling of the patient'shead. The non-vaporized liquid may then be allowed to run out thepatient's other nostril. In an alternative embodiment, the elongatetubular member may further comprise a second lumen having a portproximal to the expandable member whereby the excess liquid may besuctioned from the patient's nasal cavity. This suctioned liquid may becontinuously recycled for a successive delivery into the patient's nasalcavity without interrupting delivery.

At the proximal end, the nasal catheter may be attached to a liquiddelivery system whereby the liquid and the gas are delivered to thecatheter through their own tubes and mixed at the point ofadministration to the patient, rather than prior to use. This ensuresthat even an unstable spray can be delivered to the desired region.Furthermore, since the liquid begins to evaporate immediately uponcontact with the gas, mixing at the point of use in the patient willensure efficient use of all available cooling. In an embodimentaccording to this invention, the mixing device may be a mixing block,machined from metal or plastic or molded from plastic, including atleast two input flow channels and a single output flow channel. The twoinput flow channels may be connected to two separate tubes containing aliquid and a compressed gas. These input channels may then be joined inthe mixing block so that the liquid and gas carried by the input tubeswill be combined, after which the combined liquid/gas mixture may thenflow through the output channel. The nasal catheter may be attached tothe output channel for delivery of the combined liquid/gas mixture tothe patient's nasal cavity.

In an alternative embodiment according to this invention, a dual lumenmixing catheter may be used to individually transport the liquid and thegas to a nasal catheter. The mixing catheter may be constructed as asingle ended device, or alternatively made into a loop similar to thestandard nasal cannula for oxygen therapy. The loop configuration aidsin placement on the patient, as it may be routed over and behind theears to hold it in place. In addition, in an alternative embodimentwhere two nasal catheters, i.e., one for each nostril, are connected tothe mixing catheter, the loop configuration also helps ensure equal flowto both nasal catheters.

The dual lumen tubing, comprising lower and upper lumens, may beattached to the nasal catheter via a connecting tube. The connectingtube is a hollow, open ended tube with an outer diameter sized to fighttightly in the inner diameter of the nasal catheter. The connecting tubemay be made from metal ‘hypodermic’ tubing or a suitable plastic. Oneend of the connecting tube resides in the lower lumen of the dual lumentubing and while the other end of the connecting tube is positioned inthe nasal catheter, thus placing the nasal catheter in fluidcommunication with the lower lumen of the mixing catheter. In addition,a small hole may be drilled in the wall of the connecting tube forplacing the connecting tube in fluid communication with the upper lumenof the dual lumen tubing. In use, the gas is supplied through the lowerlumen, i.e., the gas channel, of the dual lumen tubing. The gas flowsthrough the connecting tube into the nasal catheter. A liquid issupplied through the upper lumen, i.e., liquid channel, of the duallumen tubing and flows through the small hole into the connecting tube.At this point, the gas is moving at a high velocity and the liquidexperiences high shear forces, breaking the liquid stream into smalldroplets and creating a nebulized liquid for delivery via the nasalcatheter. The inner diameter of the connecting tube and the size of thefluid hole are important parameters and may be varied to vary the sizeof the liquid droplets and to optimize the spray pattern of the nasalcatheter, for example the diameter of the connecting tube may varybetween 0.050-0.150 inches and the diameter of the fluid hole may varybetween 0.010-0.090 inches. In addition, a second fluid hole may beadded to further optimize the spray pattern.

In an alternative embodiment according to this invention, the mixing ofthe liquid and gas occurs in the distal region of the nasal catheter,proximal to the spray nozzle. Here, the lower lumen of the dual lumentubing is the liquid channel and the upper lumen is the gas deliverychannel. The lower lumen is connected to an open ended liquid deliverytube extending perpendicularly from an outlet port in the outer wall ofthe upper lumen. When the nasal catheter is secured to the outlet portin the upper lumen, the liquid delivery tube will extend coaxiallyinside the lumen of the nasal catheter. The liquid delivery tube issized to extend to the distal region of the nasal catheter and has adiameter smaller the inner diameter of the nasal catheter. In use, theliquid flows though from the liquid channel of the dual lumen tubingthrough the liquid delivery tube to the distal region of the nasalcatheter at a rate of approximately 25-200 ml/min, while the gas flowsinto the lumen of the nasal catheter at the proximal end by flowingthrough the outlet port and in the annular space between the liquiddelivery tube and the inside diameter of the nasal catheter. When theliquid and gas are combined at the end of the liquid tube, turbulenceand other flow effects, for example Bernoulli pressure, cause the fluidto be broken up into small droplets. The advantages of this embodimentare that less pressure is required to drive the liquid which may aid inmatching liquid and gas flow rates.

In an alternative embodiment according to this invention, the mixingcatheter may further include a second connecting tube or a second outletport and liquid delivery tube combination so that a second nasalcatheter, for the patient's second nostril, may be connected to themixing catheter. When two nasal catheters are used, the connecting tubesor outlet ports may be spaced apart an appropriate distance for thenares of the patient. In addition, the length of the nasal catheters maybe varied to accommodate for varying nasal cavity size in order to beable to target specific tissues in the nasal cavity.

In an alternative embodiment according to this invention, the mixingcatheter may further include a liquid delivery system for using thepressure from the compressed gas source to deliver the liquid to thenasal catheter. In this device, both the gas and the liquid aredelivered strictly using the pressure form the compressed gas sourcewithout the use of pumps or electronics. Here, an inlet valve isconnected to a compressed gas source, typically oxygen or an oxygen andair mixture regulated to about 50 psi. The inlet valve blocks or allowsthe pressurized gas into the rest of the system. When the inlet valve isin the “blocked” position, the valve also may vent pressure from thesystem. When the inlet valve is in the “allow” position, the gas flowsplits in two directions, one flow is connected to the gas flow channelof the dual lumen tubing and the other flow is connected to a fluidreservoir container which is designed to hold the desired dose of aliquid. The fluid control reservoir is rated to withstand the pressureof the compressed gas, for example the fluid control reservoir may be apoly ethylene teraphalate (PET) container tested to pressures in excessof 150 psi. In addition, a burst disk or relief valve, set at a valueexceeding the expected operating pressure, for example 60 psi,alternatively 70 psi, alternatively 80 psi, alternatively 90 psi may beadded to the fluid reservoir container as a safety means for venting gasin the event of over pressurization. Alternatively, an extra layer ofmaterial, such as a flexible membrane, mesh bag, etc may be attached tothe fluid reservoir container to contain the pieces of the container inthe event of a container rupture.

When the pressurized gas flows into the fluid reservoir, the fluid isrouted though an outlet port in the reservoir that is in fluidcommunication with the liquid channel of the dual lumen tubing. Inaddition, the outlet port may include a fluid flow controlling device,such as a needle type valve or a variable diameter aperture to adjustthe flow rate of fluid into the liquid channel of the dual lumen tubing.In addition, the flow channel to the gas channel of the dual lumentubing may also include a flow controlling device such as a needle typevalve or a variable diameter aperture to adjust the flow rate of gasinto the gas channel of the dual lumen tubing. The flow control valvesof the gas and liquid channels may be independently controlled by theoperator to allow full flexibility in varying the gas and/or liquid flowto optimize the gas/liquid flow ratio. The gas and liquid flow controldevices may have fixed orifices which produce a known constant flow forthe gas and the liquid, or alternatively, the control devices mayinclude a selector which would allow the operator to choose one ofseveral sets of orifices in order to provide the operator with a numberof choices for the flow, for example low flow, medium flow, high flow,induction and maintenance flow rates. Here, each set point on theselector would use a predetermined orifice for the gas flow and amatched orifice for the liquid such that the gas/liquid flow rates andratios would be optimized for each condition. In an alternativeembodiment, the flow rate generated by the fixed orifices may be furtheraltered while maintaining the constant gas/liquid ration, by usingpressure regulator to regulate the input pressure of the gas source. Thepressure regulator may also allow better control of the gas pressuredelivered to the liquid delivery system and to the nasal catheter.

In addition, liquid and gas flow meters may be used in the liquid andgas flow channels to further monitor and regulate the liquid and gasflow rates. The flow meter may be any standard flow technology such asturbines, paddlewheels, variable area Rota meters or mass flow meters.In addition, in line filters may be used for both the gas and liquidchannels to prevent particulate matter from being introduced to thepatient.

In an alternative embodiment, a nasal catheter may be designed toinclude an elongate tubular member extending into the patientsnasopharynx and further including having one or more parallel lumens andone or more expandable members mounted on the distal end. In use, thenasal catheter may be inserted into one of the patient's nostrils andpositioned in the posterior aspect of the nasal cavity, proximal to theopening to the nasopharynx. Once positioned in posterior aspect of thenasal cavity, the one or more expandable members may be expanded toconform to the posterior aspect of the nasal cavity and form a sealisolating the nasal cavity from the nasopharynx and the rest of thepatient's airways in order to prevent liquid from leaking into thethroat. Once isolated, a cooled liquid, for example cold saline, may bedelivered into one of the patient's nostrils via a first lumen andcirculated though the nasal cavity to allow for rapid cooling of thepatient's head. The saline may then be allowed to run out the patient'sother nostril.

In an alternative embodiment, the elongate tubular member may furthercomprise a second lumen having a port proximal to the expandable memberwhereby the excess liquid may be suctioned from the patient's nasalcavity. In addition, this suctioned liquid may be recycled forsuccessive delivery into the patient's nasal cavity. In addition, theelongate tubular member may further comprise a set of two expandablemembers located on the proximal end to occlude the nostrils and thusfurther isolate the nasal cavity and prevent fluid from leaking out ofthe patients nostrils. In this embodiment, the elongate member mayfurther include a third lumen extending between the distal and proximalends of the elongate member and having an opening at the distal andproximal ends and for providing a breathing passage through the nasalcavity while it is occluded by the expandable members. In use, thecatheter may be inserted into one of the patient's nostrils andpositioned in the posterior aspect of the nasal cavity, proximal to theopening to the nasopharynx. Once positioned in posterior aspect of thenasal cavity, the one or more distal expandable members may be expandedto conform to the posterior aspect of the nasal cavity and form a sealisolating the nasal cavity from the nasopharynx while the two proximalexpandable members may be expanded to occlude the patients nostrils andisolate the nasal cavity. Once isolated, a cold liquid, for example coldsaline or a PFC, may be delivered to the nasal cavity via a deliverylumen and suctioned out of the nasal cavity via a suction lumen. Thenasal cavity is completely isolated so none of the liquid may leak tothe throat or run out the patients nostrils however the suction lumenallows used saline to be removed from the nasal cavity so that coldsaline can be continuously introduced. Use of the distal and proximalexpandable members to isolate the nasal cavity, however, may cause apressure build up in the nasal cavity. To prevent such a pressurebuild-up, the expandable members may be made of a somewhat porousmaterial such as cork, wool, cotton or any other slightly porousmaterial known to those skilled in the art. The slightly porous materialmay prevent pressure build up while still preventing most fluid leakage.In addition, the third lumen with openings on the proximal and distalends of the elongate tubular member permits the patient to continuebreathing through his nose even while the nasal cavity is isolated fortreatment.

In an alternative embodiment, anesthetics, such as lidocaine ormarcaine, vasodilators, such as beta blockers, Nitric Oxide ornitroglycerin, neuroprotective agents and any other drugs for systemicabsorption, such as insulin, may also be delivered to the nasal cavitywith this device. It is further contemplated that these drugs may bedelivered unaccompanied or may be delivered in addition to a coolingagent to facilitate cerebral cooling.

In an alternative embodiment, a conductive gel may be delivered to theisolated nasal cavity via the delivery lumen. Once the gel has beendelivered to the nasal cavity, a conductive device that conducts heatmay be inserted to the nasal cavity via either the delivery lumen or afourth lumen to cool the conductive gel in place. The conductive devicecould be a metal, such as copper. Alternatively, the conductive devicemay be a probe through which a chilled fluid is circulated, a probe inwhich a fluid undergoes a phase change, or a heat pipe, which is asealed system utilizing an internal fluid that boils on one end andcondenses on the other end in order to transmit heat. In the case of theprobe with the fluid undergoing a phase change, the fluid may have aboiling point below body temperature, such as Freon. Additionally, anexternal cooling source, such as a refrigeration system, thermoelectricheat pump, ice bath, or evaporative cooler, will be connected to theproximal end of the probe.

In an alternative embodiment, a second nasal catheter comprising anelongate tubular member with an expandable member mounted on the distalend may be inserted in the patient's second nostril. In this embodiment,the balloons may be positioned on either side of the nasal cavity beforethe septum and expanded to isolate the nasal cavity from the rest of thepatient's airways.

The compositions of the invention include liquids having a boiling pointof 38-300° C., more preferably a boiling point of 38-200° C., morepreferably a boiling point of 60-150° C., more preferably a boilingpoint of 70-125° C., more preferably a boiling point of 75-110° C., morepreferably a boiling point of 60-70° C. Compounds having suitablecharacteristics for use herein include hydrocarbons, fluorocarbons,perfluorocarbons, and perfluorohydrocarbons. Saline is another exampleof a substance having suitable characteristics for use herein. As usedin this specification, the terms “fluorocarbon,” “perfluorocarbon,” and“perfluorohydrocarbon” are synonymous. In addition to containing carbonand fluorine, these compounds may also contain other atoms. In oneembodiment, the compounds could contain a heteroatom, such as nitrogen,oxygen, or sulfur, or a halogen, such as bromine or chlorine. Thesecompounds may be linear, branched, or cyclic, saturated or unsaturated,or any combination thereof.

In another embodiment, the compounds are highly fluorinated compounds,which are compounds containing at least three fluorine atoms. Thesehighly fluorinated compounds may also contain other atoms besides carbonand fluorine. These other atoms include, but are not limited to,hydrogen; heteroatoms such as oxygen, nitrogen, and sulfur; and halogenssuch as bromine or chlorine. In one embodiment, the number of the atomsthat are not carbon or fluorine comprise a minority of the total numberof atoms in the compound. These highly fluorinated compounds may belinear, branched, or cyclic, saturated or unsaturated, or anycombination thereof. Examples of these compounds include, but are notlimited to, C₄F₉Br (b.p. 43° C.), CF₃CF(CF₃)CF═CF₂ (b.p. 51° C.), orCF₃CF(CF₃)CH═CH₂.

In another embodiment, the compounds are hydrofluorocarbons, which arecompounds where the number of hydrogen atoms exceeds the number offluorine atoms. These hydrofluorocarbons may also contain other atomsbesides hydrogen, carbon, and fluorine. These other atoms include, butare not limited to, heteroatoms such as oxygen, nitrogen, and sulfur andhalogens such as chlorine and bromine. For example, hydrofluorocarbonsinclude, but are not limited to, hydrochlorofluorocarbons, morespecifically, hydrochlorofluoralkanes. In one embodiment, the number ofthe atoms other than carbon and fluorine comprise a minority of thetotal number of atoms in the compound. These hydrofluorocarbons may belinear, branched, or cyclic, saturated or unsaturated, or anycombination thereof.

A mixture of two or more highly fluorinated compounds,hydrofluorocarbons, light fluorocarbons, hydrocarbons, fluorocarbons,perfluorocarbons, perfluorohydrocarbons, or any of the above-mentionedcompounds may also be used. The mixture may contain any of thepreviously mentioned compounds in different phases (e.g., one gas, oneliquid). The mixture has a boiling point above 37° C., even though anyindividual component of the mixture may have a boiling point below 37°C.

Light fluorocarbons are fluorocarbons that have a boiling point below37° C. These light fluorocarbons may also contain other atoms besidescarbon, and fluorine. These other atoms include, but are not limited to,hydrogen; heteroatoms such as oxygen, nitrogen, and sulfur; and halogenssuch as chlorine and bromine. For example, light fluorocarbons include,but are not limited to perfluorobutane and perfluoropentane. In oneembodiment, the number of the atoms other than carbon and fluorinecomprise a minority of the total number of atoms in the compound. Theselight fluorocarbons may be linear, branched, or cyclic, saturated orunsaturated, or any combination thereof.

In certain methods, a liquid having a boiling point of 38-300° C., morepreferably having a boiling point of 38-200° C., more preferably havinga boiling point of 38-150° C., is selected. The liquid is nebulized toform a mist. The droplets preferably range in size from 0.1-100 microns,more preferably 1-5 microns, more preferably 2-4 microns. The mist isoptionally cooled below body temperature and delivered to the airway ofa patient so that the patient inhales the mist. Inhalation of the mistcauses systemic cooling by heat transfer from the lungs to the coolermist and/or by evaporative heat loss as the mist evaporates. The liquidis delivered at a rate to achieve 3-4° C. cerebral cooling in one houror alternatively 2° C. body cooling in one hour. The liquid deliveryrate preferably ranges from 10-500 cc/min, more preferably between50-350 cc/min, more preferably between 150-220 cc/min, more preferablyabout 175 cc/min. The administration of the liquid is continued untilthe systemic temperature is reduced to 35° C. or below, more preferablyto 34° C. or below, more preferably to 33° C. or below. The rate ofcooling can be adjusted by varying the temperature of the inhalate, theconcentration of the responsible compound or compound mixture, the rateof delivery, the particle size, and the percentage of each compound inthe mixture.

Nitric oxide or adrenergic agents, such as adrenaline (epinephrine) oralbuterol, may be added in minute doses to the compositions described inany of the previously described embodiments. The NO or other agent isinhaled and acts as a potent nasal vasodilator, which improves the rateof action of the cooling mist and counteracts nasal vasoconstrictioncaused by administering cold substances to the nasal cavity. The NO maybe included in an amount of about 2 to about 80 parts per million, inother cases in an amount of about 3 to about 20 parts per million, inother cases in an amount of about 4 to about 10 parts per million, inother cases in an amount of about 5 to about 8 parts per million, inother cases in an amount of about 5 parts per million.

In other methods, administration of cold mists will occur in cycles withintervening cycles of administering another gas, preferably a cold drygas such as dry air or dry heliox, e.g., a mixture of helium and oxygen.With continuous administration of perfluorocarbon mist, the gaseousphase in the nasal cavity may become saturated with gaseous PFC, therebyslowing the rate of evaporative heat loss. In order to accelerate therate of evaporative heat loss, it may be desired to periodically purgenasal cavity of perfluorocarbon. This can be done by cyclingadministration of cold mists with administering another gas, preferablya dry gas such as dry air or dry heliox.

Where cycling is desired, it is recommended that the cycles occur forabout 3 seconds or more, in other cases for about 30 seconds or more, inother cases for about one minute or more, in other cases for about twominutes or more, in other cases for about five minutes or more, in othercases for about ten minutes or more, in other cases for about 30 minutesor more. The intervening cycle of dry gas may last for an equal period(e.g., about 3 seconds of cold mist followed by about 3 seconds of drygas, about 30 seconds of cold mist followed by about 30 seconds of drygas, about one minute of cold mist followed by about one minute of drygas, about two minutes of cold mist followed by about two minutes of drygas, about five minutes of cold mist followed by about five minutes ofdry gas, about ten minutes of cold mist followed by about ten minutes ofdry gas, about 30 minutes of cold mist followed by about 30 minutes ofdry gas, or for a shorter or longer period (about ten minutes of coldmist followed by about two minutes of dry gas).

In certain methods, a liquid having a boiling point of 38-300° C. isselected. The liquid is nebulized to form a mist. The dropletspreferably range in size from 1-5 microns. The mist is delivered to thenasal and or oral cavities of a patient so that the mist causes cerebralcooling by heat transfer to the cooler mist and/or by evaporative heatloss. In addition indirect hematogenous cooling occurs through thecarotids as they pass by the oropharynx and through the Circle of Williswhich lies millimeters away from the pharynx. The administration of theliquid is continued until the cerebral temperature is reduced to 35° C.or below, more preferably to 34° C. or below, more preferably to 33° C.or below. In certain methods, the administration of the liquid may becontinued to provide for systemic cooling as well as cerebral cooling.In certain methods, the liquid may be cooled to below body temperaturebefore delivery. The mist droplets may range in size from 1-5 microns.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a device having multiple ports fordelivering a liquid inserted into the nasopharyngeal cavity according tothe present invention for non-invasive cerebral and systemic cooling.

FIG. 2 illustrates an embodiment of a device having multiple ports fordelivering a liquid to the nasopharyngeal cavity according to thepresent invention for non-invasive cerebral and systemic cooling.

FIG. 3 illustrates an embodiment of a device having multiple ports fordelivering a liquid to the nasopharyngeal cavity according to thepresent invention for non-invasive cerebral and systemic cooling.

FIG. 4 illustrates a cross-section of a nasal catheter having aplurality of lumens for separately transporting a liquid and acompressed gas according to the present invention.

FIG. 5 illustrates a cross-section of a nasal catheter having aplurality of ports for separately nebulizing a liquid and delivering anebulized liquid spray to the nasal cavity according to the presentinvention.

FIG. 6A illustrates a cross-section of an alternative embodiment ofnasal catheter having a plurality of lumens for separately transportinga liquid and a compressed gas according to the present invention.

FIG. 6B illustrates a cross-section of an alternative embodiment of anasal catheter having a plurality of ports for nebulizing a liquid anddelivering a nebulized liquid spray to the nasal cavity according to thepresent invention.

FIG. 7A illustrates a cross-section of an alternative embodiment ofnasal catheter having a plurality of lumens for separately transportinga liquid and a compressed gas according to the present invention.

FIG. 7B illustrates a cross-section of an alternative embodiment of anasal catheter having a plurality of ports for nebulizing a liquid anddelivering a nebulized liquid spray to the nasal cavity according to thepresent invention.

FIG. 7C illustrates a cross-section of an alternative embodiment of anasal catheter having a plurality of ports for nebulizing a liquid anddelivering a nebulized liquid spray to the nasal cavity according to thepresent invention.

FIG. 7D illustrates a cross-section of an alternative embodiment of anasal catheter having a plurality of ports for nebulizing a liquid anddelivering a nebulized liquid spray to the nasal cavity according to thepresent invention.

FIG. 8. illustrates a cross-section of an alternative embodiment ofnasal catheter having a plurality of lumens for separately transportinga liquid and a compressed gas according to the present invention.

FIG. 9 is a table of parameters and results for cerebral cooling trialsperformed wherein the compressed gas flow rate was maintained while theliquid flow rates were varied.

FIG. 10 is a graph of the nasal temperatures against liquid flow ratefor the different compressed gas flow rates listed in FIG. 9.

FIG. 11 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 12 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 13 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 14 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 15 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 16 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 17 is a graph illustrating the gradient between cerebral andsystemic cooling achieved using a method according to the presentinvention in a human.

FIG. 18 is a graph illustrating the gradient between mean cerebral andmean systemic cooling achieved using a method according to the presentinvention.

FIG. 19 is a graph illustrating the cooling rates achieved using amethod according to the present invention for various delivery rates.

FIG. 20 illustrates an embodiment of a device having a cooling helmet orcap with attached nasal prongs according to the present invention fornon-invasive cerebral and systemic cooling.

FIG. 21 illustrates an embodiment of a device having a mask with a nasalcatheter inserted therethrough.

FIG. 22A illustrates an embodiment of a device having a flexible balloonmounted on an elongate tubular member for insertion into the nasalcavity.

FIG. 22B illustrates the device of FIG. 22A inserted into a nasalcavity.

FIG. 23A illustrates an alternative embodiment of a flexible balloondevice for insertion into a nasal cavity.

FIG. 23B illustrates the device of FIG. 23A inserted into a nasalcavity.

FIG. 24 illustrates an embodiment of a device having a flexible balloonmounted on an elongate tubular member inserted down the esophagus.

FIG. 25A illustrates a modified laryngeal mask.

FIG. 25B illustrates an alternative embodiment of a modified laryngealmask.

FIG. 25C illustrates use of the device of FIG. 25A.

FIG. 26 illustrates an embodiment of a flexible balloon device forinsertion into the oral cavity.

FIG. 27 illustrates an embodiment of a device having a flexible balloonand a cold probe for insertion into the nasal cavity.

FIG. 28A illustrates an alternative embodiment of a device having aflexible balloon and a cold probe for insertion into the nasal cavity.

FIG. 28B illustrates the device of FIG. 28A inserted into a nasalcavity.

FIG. 29 illustrates an embodiment of a device having a flexible balloonmounted on a branched elongate tubular member for insertion into thenasal cavity.

FIG. 30 illustrates an alternative balloon shape.

FIG. 31 illustrates a fluid and gas delivery system.

FIG. 32A illustrates an embodiment of a device having an expandablemember constructed according to the present invention for non-invasivecerebral and systemic cooling.

FIG. 32B illustrates an embodiment of a device having an esophagealsuction tube constructed according to the present invention.

FIG. 33 illustrates an embodiment of a device having an esophagealsuction tube and a gastric suction tube constructed according to thepresent invention.

FIG. 34 illustrates an embodiment of a device having a nasal plugconstructed according to the present invention.

FIG. 35 illustrates an alternative embodiment of a device having anexpandable member constructed according to the present invention fornon-invasive cerebral and systemic cooling.

FIG. 36 illustrates an embodiment of a device for delivering a liquid tothe nasal and oral cavity according to the present invention

FIG. 37. is a table of experimental date from cerebral cooling trialsperformed wherein the cooling liquid used and the flow rate were varied.

FIG. 38 is a graph of is of brain temperatures against time fordifferent runs listed in FIG. 37.

FIG. 39 illustrates an embodiment of a device having a spray nozzleconstructed according to the present invention for non-invasive cerebraland systemic cooling via the nasal cavity.

FIG. 40 illustrates an embodiment of a delivery system constructedaccording to the present invention for delivery of a liquid and gas fornon-invasive cerebral and systemic cooling of the nasal cavity.

FIG. 41 illustrates an embodiment of a connecting tube for connectingthe nasal catheter to the liquid delivery system constructed accordingto the present invention.

FIG. 42 illustrates an embodiment of a connecting tube for connectingthe nasal catheter to the liquid delivery system constructed accordingto the present invention.

FIG. 43A illustrates an embodiment of a spray nozzle for use with thepresent invention.

FIG. 43B illustrates an embodiment of a spray nozzle for use with thepresent invention.

FIG. 43C illustrates an embodiment of a spray nozzle for use with thepresent invention.

FIG. 44 illustrates a mixing block for mixing the liquid and gas at thepoint of administration constructed according to the present invention.

FIG. 45 illustrates a liquid delivery system for delivering the liquidto the point of administration constructed according to the presentinvention.

FIG. 46 illustrates an embodiment of a device having an expandablemember constructed according to the present invention for non-invasivecerebral and systemic cooling via the nasal cavity.

FIG. 47 illustrates an embodiment of a device having proximal and distalexpandable members constructed according to the present invention fornon-invasive cerebral and systemic cooling via the nasal cavity.

FIG. 48 illustrates an embodiment of a device having proximal and distalexpandable members constructed according to the present invention fornon-invasive cerebral and systemic cooling via the nasal cavity.

DETAILED DESCRIPTION Evaporative Cooling in the Nasal Cavity

FIGS. 1-3 illustrate nasal catheter 10 with multiple delivery ports 12a-m for non-invasive cerebral and systemic cooling of the nasal cavity.Nasal catheter 10 is operably sized to extend through the patient'snasal cavity and into the nasal pharynx and has a plurality of lumens 14and 16 a-b extending between the proximal and distal ends of catheter 10for separately delivering a liquid and a compressed gas. Nasal catheter10 also has rounded sealed tip 22 on the distal end, which seals thedistal end of lumens 14 and 16 a-b and provides a smooth surface toavoid damaging sensitive tissues. FIGS. 4-7 depict several possibledesigns for the lumens of nasal catheter 10. FIG. 4 shows catheter 10with a large, circular central lumen 14 that may be used fortransporting the compressed gas through catheter 10 while one or moresmaller lumens 16 a-b may be used for transporting the liquid throughcatheter 10. In FIGS. 6-8, more complex, geometric extruded tubes areused to simplify the mixing process at each delivery port. In FIGS.6A-B, square central lumen 64 is provided for transporting thecompressed gas through the catheter while the liquid may be transportedin four outer sections 66 a-d. FIGS. 7A-D depict an alternativeembodiment where the gas lumen is a central geometric shape 74 and thefour outer sections 76 a-d form the channels for transporting theliquid. In an alternative embodiment, additional lumens (not shown) maybe provided, for example, to permit inflation of an expandable memberlocated on the distal end of the catheter or to permit suction of thenon-evaporated liquid from the nasal cavity.

As shown in FIG. 3, a plurality of ports 12 a-m are located along theouter wall of catheter 10. These ports 12 a-m are spaced apartlongitudinally and axially along the outer walls of catheter 10 and arein fluid communication with lumens 14 and 16 a-b transporting the liquidand compressed gas through catheter 10. For example, there may be about10-40 delivery ports distributed around the circumference of thecatheter and spaced apart to cover the distance from about 3 cm to about12 cm along the length of catheter 10. In use, when catheter 10 isplaced in the nasal cavity of a patient, this distribution would providefull coverage of the nasal cavity. Furthermore, each delivery port willbe designed so that the liquid and gas flowing through the catheterlumens will be combined near the delivery port and the liquid will thenbe nebulized just prior to entering the nasal cavity. As shown in FIG.5, each of ports 12 a-m is formed by drilling mixing channel 18 in theouter wall of nasal catheter 10 connecting to central lumen 14transporting the compressed gas. In addition, separate liquid connectingtubes 20 are formed in the outer wall of catheter 10 to connect liquidlumens 16 a-b with each of mixing channels 18 drilled between ports 12a-b and compressed gas lumen 14. This provides for the ability toseparately nebulize the liquid into a spray at each delivery port.Specifically, mixing channels 18 provide for gas flow outward fromcentral gas lumen 14 while liquid connecting tubes 20 permit addition ofthe liquid to the gas stream in channel 18. At this point, the gas ismoving at a high velocity and the liquid experiences high shear forces,breaking the liquid stream into small droplets and creating a nebulizedliquid for delivery via ports 12 a-b. The inner diameter of connectingtubes 20 and the shape and size of the ports 12 a-b are importantparameters and may be altered to vary the size of the liquid dropletsand to optimize the spray pattern of delivery ports 12 a-b.

FIGS. 6A-B and 7A-D depict alternative configurations for the liquid andgas channels within the nasal catheter and delivery ports on the outerwalls of the catheter that may provide for easier mixing of the liquidand compressed gas at the delivery port. In FIGS. 6A-B, the nasalcatheter is formed of a length of extruded tubing with interior sidewalls 63 a-d creating a central square lumen 64 in which the compressedgas may be transported and four separate outer channels 66 a-d in whichthe liquid may be transported. Here, when mixing channel 68 is drilledthrough the outer wall of the catheter at one of the corners where twoof side walls 63 a-b of the central lumen 64 connect with the outer wallof the catheter, openings 60 a and 60 b are created in each of theadjacent interior channels 66 a-b through which liquid can enter the gasstream flowing through mixing channel 68. This design simplifies theconstruction of the device by eliminating the need for a separateconnecting tube to connect the liquid lumens with the mixing channel.Moreover, the size of mixing channels 60 a-b may be altered to providefor a desired liquid flow rate by adjusting the diameter of mixingchannel 68. FIGS. 7A-D depict an alternative embodiment of a nasalcatheter with a shaped central lumen 74 for transporting the compressedgas surrounded by four outer channels 76 a-d for transporting theliquid. Delivery ports 72 are created by making skyved cuts 73 in theouter wall of the catheter, which creates aperture 77 from the gas lumen74 and openings 75 a-b into the outer channels 76 a-d transporting theliquid from which the liquid can enter into the gas stream. As depictedin FIG. 7B-D, the skyved cuts may be rectangular 73, circular 78, orV-shaped 79, and may be of varying sizes to affect both the velocity ofthe nebulized liquid, flow rate, and size of the spray particles.

In another alternative embodiment, depicted in FIG. 8, central lumen 84may be used to transport the liquid, while four outer channels 86 a-dare used to transport the compressed gas. Delivery port 82 is created bymaking a skyved cut in the outer wall of the catheter at the junction ofthe central lumen 84 and two adjacent liquid channels 86 a-d. The skyvedcut provides an aperture through which the compressed gas from outer gaschannels 86 a-d can escape and also creates central slit 85 in fluidcommunication with central lumen 84 for introducing the liquid fromcentral lumen 84 into the gas stream. In addition to reducing themanufacturing complexity by eliminating the need for a separate channelbetween the liquid and gas lumens, this may be advantageous forproviding a wider dispersion of flow from each delivery port 82.

The liquids used with this catheter include liquids having a boilingpoint of about 38-300° C., more preferably a boiling point of about38-200° C., more preferably a boiling point of about 60-150° C., morepreferably a boiling point of about 70-125° C., more preferably aboiling point of about 75-110° C., more preferably a boiling point ofabout 60-70° C. Compounds having suitable characteristics for use hereininclude hydrocarbons, fluorocarbons, perfluorocarbons, andperfluorohydrocarbons. Saline is another example of a substance havingsuitable characteristics for use herein. As used in this specification,the terms “fluorocarbon,” “perfluorocarbon,” and “perfluorohydrocarbon”are synonymous. In addition to containing carbon and fluorine, thesecompounds may also contain other atoms. In one embodiment, the compoundscould contain a heteroatom, such as nitrogen, oxygen, sulfur, or ahalogen, such as bromine or chlorine. These compounds may be linear,branched, or cyclic, saturated or unsaturated, or any combinationthereof. Exemplary perfluorocarbons include perfluoropropane,perfluorobutane, perfluoropentane, 2-methyl-perfluoropentane,perfluorohexane, perfluoroheptane, and perfluorooctane.

The liquids delivered through the catheter (single or multi-lumen) mayalso comprise a humidifier. Alternatively, the humidifier may bedelivered separately through the catheter or using an alternativedelivery device. When used in conjunction with the cooling liquid, thehumidifier would have to be cooled or else it would counteract thecooling effect of the other liquid. Where the humidifier was usedindependently for humidification, it could also be warmed. Thehumidifiers may be delivered through the same ports in the catheter asthe cooling liquid. Alternatively, a different lumen and/or port in thecatheter may be used to deliver the humidifier. The purpose of thehumidification is to prevent the sensation of dryness, the crusting andtrauma that could result from the dryness, the nasal congestion andmucous production that could result from dryness imparted by the highgas flow rates or from the evaporation of the liquid (e.g., PFC). Thecongestion and mucous production reduce the effectiveness of the coolingby limiting the cavity in which the evaporation occurs and by directlyblocking holes in the catheter. This phenomenon may account for rapidinitial cooling rates observed, followed by slower cooling rates beyondthe first 20 to 30 minutes.

The humidifier may be, but is not limited to isotonic saline, or water.Where water is used as the humidifier, the quantity needed to be addedfor full saturation is about 41 micrograms/L of gas. Alternative nasalinhalers, such as but not limited to, ephedrine, pseudoephedrine (e.g.,Afrin), antihistamines, ipratropium (e.g., Atrovent), andanticholinergics, may also be used to saturate the air in the nasalcavity.

The gases used with the catheter include any gas capable of evaporatingthe liquid. The gas can include, but is not limited to, nitrogen, air,oxygen, argon, or mixtures thereof.

In use, as seen in FIG. 1, this catheter is intended to be placedthrough the patient's nostrils and extend through the narices of thenose to the nasopharyngeal region of the nasal cavity. The length ofcatheter 10, which extends to the nasal pharyngeal region of the nasalcavity and multiple ports 12 a-m located longitudinally and axiallyalong the outer wall of the catheter enable catheter 10 to disperse theliquid spray perpendicular to the longitudinal axis of catheter 10 andover the entire nasal cavity region. This is in contrast to simplydirecting the spray through a single spray nozzle at a catheter tip,which would have the spray limited to a particular area along thelongitudinal axis of catheter. This distinction is critical in thatdispersing the spray over a larger region permits greater cooling thoughevaporative heat loss.

In addition, the ability to nebulize the liquid at each delivery portensures that the distribution of varying sizes of liquid particles willbe uniform throughout the nasal cavity. Specifically, when a liquid isnebulized, a spray with liquid particles of various sizes is created. Ifthe liquid was nebulized at the proximal end of the nasal catheter oroutside of the catheter and then transported as a nebulized liquid spraythrough the catheter lumen to the multiple delivery ports, the smallerliquid particles would flow through the proximal delivery ports whilethe larger liquid particles would be carried to the distal end of thetube before being delivered to the nasal cavity via one of the deliveryports near the distal end of the nasal catheter. This would result in anuneven distribution of the liquid particles within the nasal cavity.Conversely, when the liquid is transported through the nasal catheterand nebulized separately at each delivery port just prior to delivery,the size distribution of liquid particles distributed at any given pointin the nasal cavity is uniform. This is critical because an evendistribution of the varying sized liquid particles provides for betterevaporation of the liquid spray, which results in better cooling throughevaporative heat loss and is more tolerable to the patient. Furthermore,since the liquid begins to evaporate immediately upon contact with thegas, mixing at the point of use in the patient will ensure efficient useof all available cooling.

The liquid flow rate is also a critical factor for cerebral cooling.FIG. 10 depicts the amount of nasal cooling per different liquid flowrates. The gradient between the cerebral and systemic cooling that formsover time is desirable in order to minimize damage to other organs andhypothermia during the cerebral cooling. In order to create a gradientbetween the cerebral and systemic temperature, the cerebral cooling mustbe induced rapidly, for example at a rate of at least about 1° C. inhour, alternatively at least about 1.5° C. in hour, alternatively atleast about 2° C. in hour, alternatively at least about 3° C. in hour,alternatively at least about 4° C. in hour, alternatively at least about5° C. in hour between the cerebral temperature and the systemictemperature. This sudden initial exposure to cold induces avasoconstriction response in the carotid arteries causing the carotidarteries to constrict, which helps isolate the cerebral vasculature andprevent warmer blood from the heart traveling to the brain and thecooler blood in the brain from traveling to and thereby cooling the restof the body. This initial vasoconstriction response thus further aidsthe cooling process by preventing warmer blood from traveling to thehead. In addition, the initial cooling lowers the metabolic demand ofthe head, thus the carotid artery can further constrict and furtherisolate the head. After the initial induction, in order to maintainsufficient cooling, the spray may be delivered at a lower flow rate. Thelower flow rate may result in a gradient between the cerebral andsystemic temperature of at least about 0.1° C., alternatively at leastabout 0.2° C., alternatively at least about 0.3° C., alternatively atleast about 0.4° C., alternatively at least about 0.5° C., alternativelyat least about 0.6° C., alternatively at least about 1.0° C.,alternatively at least about 1.5° C., alternatively at least about 2.0°C., alternatively at least about 2.5° C., alternatively at least about3.0° C., alternatively at least about 3.5° C., alternatively at leastabout 4.0° C., alternatively at least about 4.5° C., alternatively atleast about 5.0° C.

In addition to the liquid flow rate, it has also been shown that theratio of gas flow rate to liquid flow rate is a critical factoraffecting the cerebral cooling within the nasal cavity. Initially, itwas thought that increasing the liquid flow rate would increase cooling.The cooling rate, however, only increases if the gas flow isconcurrently increased to evaporate the nebulized liquid. This isnecessary because the cooling within the nasal cavity is achievedthrough evaporative heat loss as nebulized liquid evaporates. If thenasal cavity becomes saturated with the evaporated liquid, however, thenthe evaporation rate decreases and consequently, the cooling ratedecreases. Thus, the rate of evaporation is dependant on theconcentration of the liquid within the nasal cavity as well as the flowrate of the liquid. Therefore, increasing the liquid flow rate to thenasal cavity only increases the cooling rate if the gas flow rate isalso increased to evaporate off the nebulized liquid. The ratio for theliquid delivery rate:gas delivery rate to optimize the evaporation andmaintain a constant rate of evaporation preferably ranges from 1:25mL-1:5000 mL, more preferably from 1:500 mL-1:200 mL, more preferablyfrom 1:700 mL-1:1500 mL. FIGS. 9-10 depict the varying cooling in anartificial nasal cavity at three different gas flow rates (40 L/min, 30L/min, and 50 L/min) as the liquid flow rate is varied. The goal is tohave 100% evaporation (i.e., “spray”). It is desirable to have themaximum amount of cooling with the least amount of liquid used.Therefore, the gas flow rate should be at least about 30 L/min,alternatively at least about 40 L/min, alternatively at least about 50L/min. The liquid flow rate should be at least about 40 mL/min,alternatively at least about 50 mL/min, alternatively at least about 60mL/min, alternatively at least about 70 mL/min, alternatively at leastabout 80 mL/min, alternatively at least about 90 mL/min, alternativelyat least about 100 mL/min.

The flow rate of the gas and liquid can be altered during the processaccording to the amount of cooling achieved. Feedback can be provided inthe form of nose temperature, body temperature, brain temperature,rectal temperature, etc. For example, an alarm could be triggered whenthe body temperature falls below 35° C. and delivery of the fluids andgas could be stopped. Additionally, or in the alternative, feedback inthe form of the brain temperature could be provided such that the rateof delivery of the fluids and gases increases if the cooling rate of thebrain is less than about 5° C. in one hour, alternatively less thanabout 4° C. in one hour, alternatively less than about 3° C. in onehour, alternatively less than about 2° C. in one hour, alternativelyless than about 1° C. in one hour.

Cooling Calculations

The following calculations estimate the maximum cooling that can beobtained using a unit dose of 2 liters of perfluorohexane. The coolingeffect of PFH is related to two aspects of thermodynamics: (1) heatcapacity of the liquid, as it is warmed from its temperature atapplication to that of the body and (2) heat of vaporization as itchanges from the liquid to the gas state. The relevant properties ofperfluorohexane are as follows:

-   -   ρ, Density: 1.68 grams/ml    -   c, Specific Heat: 1.09 kJ/kg° C.=0.26 cal/g° C.    -   h, Latent Heat: 85.5 kJ/kg=20.4 cal/g

The calculation for heat transfer due to warming the liquid is:

Q=c*m*(T2−T1) or Q=cmΔT  Equation 1

Where m=the mass of the liquid administered

-   -   T1 is the temperature of the liquid at administration    -   T2 is the temperature to which the liquid is warmed

In the patient case, the heat removed is calculated using the followingassumptions: (1) a unit dose quantity of 2 liters is used; (2) the PFCis administered at 0° C.; and (3) the PFC is warmed completely to bodytemperature of 37° C.

Q=2000 ml*1.68 g/ml*0.26 cal/g° C.*(37° C.−0° C.)=32,300 calories

The calculation for heat transfer due to evaporation of the liquid is:

Q=h*m  Equation 2

Therefore, assuming a dose of 2 liters,

Q=2000 ml*1.68 g/ml*20.5 cal/g=68,900 calories

For a 2 liter quantity of liquid, the maximum heat removal=100,000calories or 100 Kcal. The amount of cooling to the body can becalculated using the following assumptions: (1) patient weight of 70 Kg,(2) specific heat of patient=0.83 cal/g° C., (3) heat generated bymetabolism or other sources is negligible, and (4) other heat added orremoved from the patient is negligible. After rearranging Equation 1(ΔT=Q/(c*m)), the net change in temperature of the whole body of thepatient can be calculated as follows:

ΔT=100 kcal/(0.83 cal/g° c.*70 kg)=1.72° C.

Therefore, the maximum whole body cooling that could occur from a 2liter dose is approximately 1.7° C. This should result in a bodytemperature no lower than 35° C., which should not cause any coldrelated complications.

The sensitivity, i.e., the resultant temperature change experienced bythe patient, will depend on the size of the patient. For a very smallpatient of 40 Kg (88 pounds), the resultant temperature change is ΔT=100kcal/(0.83 cal/g° c.*40 kg)=2.1° C. For a very large patient of 100 Kg,the resultant temperature change is ΔT=100 kcal/(0.83 cal/g° c.*100kg)=0.83° C.

By applying the cooling spray to the nasal cavity, there will be morecooling in the head than the remainder of the body. Calculations can bedone to determine how cold the head might become if all the cooling isfocused solely in the head. The amount of cooling to the head can becalculated using the following assumptions: (1) mass of head=5 kg, (2)specific heat of head=0.83 (same as rest of body), and (3) heat transferfrom body (warming from cerebral blood flow) is negligible.

ΔT=q/(s*m)=100 kcal/(0.83 cal/g° C.*5 kg)=24 Degrees C.

This corresponds to a potential minimum head temperature of 13° C.

The above calculations assume that every bit of the liquid is warmedfully to body temperature and evaporates completely. It is likely thatin a clinical setting, there will be incomplete warming and evaporation.Specifically, some of the gas and vapor leaving the body will not be at37° C., and some of the liquid will trickle out of the patient withoutcontributing to heat transfer. These effects will tend to reduce thecooling from the calculated values.

The head cooling calculation assumes that absolutely no heat will beadded to the head from the body. This is, however, a poor assumption.The cerebral blood flow is on the order of 1 L per minute, and assumingthat this blood is cooled by only 2 degrees while in the head, thecalculation becomes as follows:

Net heat removal=100 Kcal−1000 ml/min*30 min*0.83 cal/g° C.*2° C.=50Kcal

Therefore, the cooling in the head is reduced by at least half of thepreviously calculated value to 12° C., for a minimum possible 25° C.head temperature

Experimental Data

In use, the nasal catheter of the present invention was inserted throughthe nose into the nasal cavity. Temperature was measured at baseline (3times over 10 minutes) and at every minute or continuously at theventricle or epidural space, where available, and bladder or rectumduring the procedure. A suction catheter was positioned in the patient'smouth to prevent pharyngeal liquid from entering the esophagus and anasogastric (NG) tube was placed in the patient's stomach to suction anyliquid PFC or PFC vapor. NG suction was continuous. Nasal cooling wasadministered via a nasal catheter with one oxygen/PFC mixer and fanspray nozzle per naris. Nasal prongs were positioned in the narices andsecured to the nose by tape. After measurement of baseline temperatures,cooling was initiated. Temperature was monitored until it returned tothe baseline value. A portion of the PFC was recovered from the oralsuction catheter placed in the back of the patient's throat. Thisrecovered PFC can be reused and recycled. The following parameters wereused for the human studies.

Oxygen was delivered at about 20 L/min throughout the delivery period,alternatively at about 30 L/min throughout the delivery period,alternatively at about 40 L/min throughout the delivery period,depending on the patient.

The PFC (e.g., perfluorohexane) was delivered at a rate of about 15mL/min, alternatively at about 25 mL/min, alternatively at about 35mL/min, alternatively at about 45 mL/min, alternatively at about 50mL/min, alternatively at about 55 mL/min, alternatively at about 65mL/min, alternatively at about 75 mL/min, alternatively at about 80mL/min, alternatively at about 85 mL/min, alternatively at about 95mL/min, alternatively at about 100 mL/min, depending on the patient. Theliquid flow rate was sometimes started at a lower flow rate (e.g., about15 mL/min or about 25 mL/min) and increased to a faster flow rate (e.g.,about 45 mL/min, about 50 mL/min, or about 100 mL/min). Alternatively,the liquid flow rate was started at a faster flow rate (e.g., about 50mL/min) and gradually reduced to a slower flow rate (e.g., about 25mL/min). A total of amount of about 1.0 L of PFC was delivered,alternatively about 1.5 L, alternatively about 2.0 L, depending on thepatient.

The delivery period was approximately 20 minutes, alternativelyapproximately 25 minutes, alternatively approximately 30 minutes,alternatively approximately 35 minutes, alternatively approximately 40minutes, alternatively approximately 45 minutes.

In one method, oxygen is delivered at about 40 L/min and PFC isdelivered at about 80 mL/min throughout the delivery period. A total ofabout 2 L of PFC is delivered. The delivery period is approximately 20to 25 minutes.

FIGS. 11-17 illustrate the gradient between the cerebral and systemictemperatures achieved using the methods described above. The rectanglesat the bottom of the graphs indicate the delivery periods for thatparticular therapy. FIG. 18 illustrates the mean cerebral and systemiccooling achieved from the experiments illustrated in FIGS. 11-17. FIG.19 illustrates the cooling temperatures achieved using various deliveryrates. As apparent from the figures, selective cooling of the brain isachieved and maintained over time, even after delivery of the coolingagents has stopped. Typically, a gradient between cerebral and systemictemperature of at least about 0.5° C. can be achieved, alternativelyabout 1.0° C. can be achieved, alternatively about 1.5° C. can beachieved, alternatively about 2.0° C. can be achieved, alternativelyabout 2.5° C. can be achieved.

The catheter of the present invention can also be used in combinationwith other cooling or heating devices. For example, the catheter may beused in combination with a helmet or cooling cap for synergistic coolingas seen in, for example, U.S. Pat. No. 6,962,600, which is herebyexpressly incorporated by reference in its entirety. As seen in FIG. 20,a cooling system 100 comprising a cooling helmet or cap 102 with thenasal catheters or prongs 110 of the present invention attached directlyto the cooling helmet or cap. Alternatively, the nasal catheters orprongs may not be attached to the cooling cap or helmet, and still beused in conjunction with the cooling cap or helmet for synergisticcooling (not shown). The cooling system 100 includes a re-circulatingliquid refrigerant container 104 with an input line 106 and an outputline 108 running from the container 104 to the cooling helmet or cap102. Alternatively, the helmet may only have an input line where coolingis accomplished through evaporation of the liquid refrigerant within thewalls of the cooling helmet or cap (not shown). Additionally, the nasalcatheters may be used in combination with a warming blanket to enhancethe gradient between the cerebral temperature and the systemictemperature where systemic cooling is inadequate to bring down the braintemperature. In one embodiment, a heat pump could be used in conjunctionwith a cooling helmet or cap and a warning blanket. The heat pump couldtake heat from the liquid being circulated to the cooling helmet or capand pump the heat into the warming blanket. The heat pump could use arefrigerant or thermoelectric cycle.

In another alternative embodiment, a mask can be used in conjunctionwith the catheter (single or multi-lumen) to increase the amount ofair/oxygen/gas delivered to the nasal cavity. This would result in anincrease in the rate of liquid evaporation, and therefore the rate ofcooling, without increasing the intranasal pressure. As see in FIG. 21,mask 280, such as a continuous positive airway pressure (CPAP) nasalmask, can have catheter 282 fitted therethrough. The positive pressureis given through mask 280. The pressures given through the mask may beabout 0 to about 200 cm H₂O, alternatively about 0 to about 150 cm H₂O,alternatively about 0 to about 100 cm H₂O, alternatively about 0 toabout 75 cm H₂O, alternatively about 0 to about 60 cm H₂O, alternativelyabout 0 to about 50 cm H₂O, alternatively about 0 to about 40 cm H₂O.Valve 284, preferably a one-way valve, at the side of mask 280 can openat a given pressure, thereby releasing excess gas into the atmosphere.Valve 284 acts as a safeguard against high intranasal pressures thatcould conceivably lead to gas entrapment in the tissue or entry into thevenous vasculature, resulting in a pulmonary embolism. Valve 284 mayopen when the pressure inside the mask reaches about 55 cm H₂O,alternatively about 60 cm H₂O, alternatively about 65 cm H₂O. In use,mask 280 is placed over the nose and nasal catheter 282 is inserted intothe nasal cavity, as described previously. Air and gas are expiredthrough the mouth, as in standard CPAP treatment.

The catheters of the present invention can also be used as drug deliverycatheters for delivery of nebulized drugs to the nasal cavity. It isfurther contemplated that these drugs may be delivered unaccompanied ormay be delivered in addition to a cooling agent to facilitate cerebralcooling. As discussed previously, the ability to nebulize the liquid ateach delivery port ensures that the distribution of varying sizes ofliquid particles will be uniform throughout the nasal cavity, whichprovides for better evaporation of the liquid spray. The drug deliverycatheter may include, but is not limited to, at least 20 delivery ports,alternatively at least 30 delivery ports, alternatively at least 40delivery ports, alternatively at least 50 delivery ports, alternativelyat least 60 delivery ports. Use of such a drug delivery catheter withnebulizing delivery ports may provide more accurate dosing than existingnasal delivery systems, which suffer from problems of liquid drippingdown the patient's throat.

The drug could be provided in a liquid suspension or a mixture. Theliquid suspension could utilize various liquid carriers, depending onthe drug. Liquid carriers include, but are not limited to, water,saline, PFC, and combinations thereof. Use of saline as a carrier has anadvantage in that may drugs are already sold with saline as the carrier.Additionally, there are no suspension problems. Use of a PFC as acarrier has an advantage in that, because the PFC would evaporate, thedrug would not be diluted.

Drugs that may be delivered using an intranasal delivery catheterinclude, but are not limited to, neuroprotective agents and malignanthyperthermia, insulin, β-blockers, β-agonists, antihistamines,contraceptives, anesthetics, painkillers, antibiotics, steroids,aspirin, sumatriptan, Viagra, nitroglycerin, hormones, neurodrugs,anti-convulsants, prozac, anti-epileptics, analgesics, NMDA antagonists,narcan, noxone, naltrexone, anxiolytics, and muscle relaxants.

Other Nasal Catheter Designs

In an alternative embodiment, as seen in FIGS. 32A-B and 33-36,specialized nasal catheter 800 is described for the application of anebulized liquid, preferably a perfluorocarbon (PFC), for cerebral andsystemic cooling. This embodiment comprises a multi-lumen elongatemember 802 with a length operable to extend a patient's esophagus to beinserted through the nose, and into the esophagus 804. Here, balloon 806is located near the distal end. This may be used to occlude theesophagus 804. Catheter 800 includes at least a first, second, and thirdlumen. First lumen 810 of the elongate member may then be used forsuctioning vapor and or liquid from the stomach. Second lumen 812 may beexposed proximal to balloon through port 814, to allow suctioning vaporor liquid which enters the upper esophagus. Third lumen 816, which is influid communication with multiple ports along catheter 800, may be usedas a spray lumen. Fourth lumen is a balloon inflation lumen and is influid communication with a chamber defined by balloon 806. In operation,catheter 800 is placed and balloon 806 inflated to occlude therespective passage, i.e., the esophagus. Gastric suction through lumen810 can be applied per clinical practice. Air (or oxygen) is introducedto the patient through the spray lumen 816 and multiple ports 820positioned in the nasal cavity. A PFC liquid is added to spray lumen816; this will produce a fog of droplets in the nasal cavity. Much ofthe PFC liquid will impact and coalesce on the walls of the nasal cavityand associated passages. This will then drain down to the throat, themajority of which will enter the esophagus where it can be suctionedthrough the proximal suction port and reused. Some of the PFC may enterthe lungs either directly as liquid or as droplets carried on theinhaled breath

In addition, as seen in FIGS. 33-36, plug or balloon 822 may be locatedat the entrance to the nasal cavity to prevent any retrograde flow outof the nose. In an alternate embodiment, the elongate member may bebifurcated outside the nose, with an additional prong and balloon (notshown) for the other nostril. Furthermore, as seen in FIG. 36, catheter830 may be bifurcated near the proximal end into two tubular members 832and 834 for delivery of liquid and/or oxygen to the nasal and oralcavities, respectively. With respect to the oral cavity, a secondelongate member could be slidably inserted into tubular member 834 fordelivering liquid and/or oxygen to the oral cavity. Alternatively, theelongate tubular member inserted into the oral cavity may be independentof the nasal catheter (not shown).

The advantages of this invention include: relative ease of placement;available port provides same function as nasogastric tube; similarity tostandard nasogastric tubes in design and use; ease of breathing,speaking, etc., through mouth for the patient; liquid flow rate is notdependant on ventilation and can be set by clinician; high turnover flowthrough cooling enabled; utilization of well perfused anatomicalfeatures; perfluorocarbon is well tolerated in lungs; perfluorocarbon inthe stomach is also tolerated, and can be easily suctioned with thegastric portion of the catheter.

The compositions of the invention include liquids having a boiling pointof about 38-300° C., more preferably a boiling point of about 38-200°C., more preferably a boiling point of about 60-150° C., more preferablya boiling point of about 70-125° C., more preferably a boiling point ofabout 75-110° C., more preferably a boiling point of about 60-70° C.Compounds having suitable characteristics for use herein includehydrocarbons, fluorocarbons, perfluorocarbons, andperfluorohydrocarbons. Saline is another example of a substance havingsuitable characteristics for use herein. As used in this specification,the terms “fluorocarbon,” “perfluorocarbon,” and “perfluorohydrocarbon”are synonymous. In addition to containing carbon and fluorine, thesecompounds may also contain other atoms. In one embodiment, the compoundscould contain a heteroatom, such as nitrogen, oxygen, or sulfur, or ahalogen, such as bromine or chlorine. These compounds may be linear,branched, or cyclic, saturated or unsaturated, or any combinationthereof.

In another embodiment, the compounds are highly fluorinated compounds,which are compounds containing at least three fluorine atoms. Thesehighly fluorinated compounds may also contain other atoms besides carbonand fluorine. These other atoms include, but are not limited to,hydrogen; heteroatoms such as oxygen, nitrogen, and sulfur; and halogenssuch as bromine or chlorine. In one embodiment, the number of the atomsthat are not carbon or fluorine comprise a minority of the total numberof atoms in the compound. These highly fluorinated compounds may belinear, branched, or cyclic, saturated or unsaturated, or anycombination thereof. Examples of these compounds include, but are notlimited to, C₄F₉Br (b.p. 43° C.), CF₃CF(CF₃)CF═CF₂ (b.p. 51° C.), andCF₃CF(CF₃)CH═CH₂.

In another embodiment, the compounds are hydrofluorocarbons, which arecompounds where the number of hydrogen atoms exceeds the number offluorine atoms. These hydrofluorocarbons may also contain other atomsbesides hydrogen, carbon, and fluorine. These other atoms include, butare not limited to, heteroatoms such as oxygen, nitrogen, and sulfur andhalogens such as chlorine and bromine. For example, hydrofluorocarbonsinclude, but are not limited to, hydrochlorofluorocarbons, morespecifically, hydrochlorofluoralkanes. In one embodiment, the number ofthe atoms other than carbon and fluorine comprise a minority of thetotal number of atoms in the compound. These hydrofluorocarbons may belinear, branched, or cyclic, saturated or unsaturated, or anycombination thereof.

A mixture of two or more highly fluorinated compounds,hydrofluorocarbons, light fluorocarbons, hydrocarbons, fluorocarbons,perfluorocarbons, perfluorohydrocarbons, or any of the above-mentionedcompounds may also be used. The mixture may contain any of thepreviously mentioned compounds in different phases (e.g., one gas, oneliquid). The mixture has a boiling point above 37° C., even though anyindividual component of the mixture may have a boiling point below 37°C.

Light fluorocarbons are fluorocarbons that have a boiling point below37° C. These light fluorocarbons may also contain other atoms besidescarbon, and fluorine. These other atoms include, but are not limited to,hydrogen; heteroatoms such as oxygen, nitrogen, and sulfur; and halogenssuch as chlorine and bromine. For example, light fluorocarbons include,but are not limited to perfluorobutane and perfluoropentane. In oneembodiment, the number of the atoms other than carbon and fluorinecomprise a minority of the total number of atoms in the compound. Theselight fluorocarbons may be linear, branched, or cyclic, saturated orunsaturated, or any combination thereof.

In certain methods, a liquid having a boiling point of 38-300° C., morepreferably having a boiling point of 38-200° C., more preferably havinga boiling point of 38-150° C., is selected. The liquid is nebulized toform a mist. The droplets preferably range in size from 0.1-100 microns,more preferably 1-5 microns, more preferably 2-4 microns. The mist isoptionally cooled below body temperature and delivered to the airway ofa patient so that the patient inhales the mist. Inhalation of the mistcauses systemic cooling by heat transfer from the lungs to the coolermist and/or by evaporative heat loss as the mist evaporates. Theadministration of the liquid is continued until the systemic temperatureis reduced to 35° C. or below, more preferably to 34° C. or below, morepreferably to 33° C. or below. The rate of cooling can be adjusted byvarying the temperature of the inhalate, the concentration of theresponsible compound or compound mixture, the rate of delivery, theparticle size, and the percentage of each compound in the mixture.

Nitric oxide or adrenergic agents, such as adrenaline (epinephrine) oralbuterol, may be added in minute doses to the compositions described inany of the previously described embodiments. The NO or other agent isinhaled and acts as a potent nasal vasodilator, which improves the rateof action of the cooling mist and counteracts nasal vasoconstrictioncaused by administering cold substances to the nasal cavity. The NO maybe included in an amount of about 2 to about 80 parts per million, inother cases in an amount of about 3 to about 20 parts per million, inother cases in an amount of about 4 to about 10 parts per million, inother cases in an amount of about 5 to about 8 parts per million, inother cases in an amount of about 5 parts per million.

In other methods, administration of cold mists will occur in cycles withintervening cycles of administering another gas, preferably a cold drygas such as dry air or dry heliox, e.g., a mixture of helium and oxygen.With continuous administration of perfluorocarbon mist, the gaseousphase in the nasal cavity may become saturated with gaseous PFC, therebyslowing the rate of evaporative heat loss. In order to accelerate therate of evaporative heat loss, it may be desired to periodically purgenasal cavity of perfluorocarbon. This can be done by cyclingadministration of cold mists with administering another gas, preferablya dry gas such as dry air or dry heliox.

Where cycling is desired, it is recommended that the cycles occur forabout 3 seconds or more, in other cases for about 30 seconds or more, inother cases for about one minute or more, in other cases for about twominutes or more, in other cases for about five minutes or more, in othercases for about ten minutes or more, in other cases for about 30 minutesor more. The intervening cycle of dry gas may last for an equal period(e.g., about 3 seconds of cold mist followed by about 3 seconds of drygas, about 30 seconds of cold mist followed by about 30 seconds of drygas, about one minute of cold mist followed by about one minute of drygas, about two minutes of cold mist followed by about two minutes of drygas, about five minutes of cold mist followed by about five minutes ofdry gas, about ten minutes of cold mist followed by about ten minutes ofdry gas, about 30 minutes of cold mist followed by about 30 minutes ofdry gas, or for a shorter or longer period (about ten minutes of coldmist followed by about two minutes of dry gas).

In certain methods, a liquid having a boiling point of 38-300° C. isselected. The liquid is nebulized to form a mist. The dropletspreferably range in size from 1-5 microns. The mist is delivered to thenasal and or oral cavities of a patient so that the patient. of the mistcauses cerebral cooling by heat transfer to the cooler mist and/or byevaporative heat loss. In addition indirect hematogenous cooling occursthrough the carotids as they pass by the oropharynx and through theCircle of Willis which lies millimeters away from the pharynx. Theadministration of the liquid is continued until the cerebral temperatureis reduced to 35° C. or below, more preferably to 34° C. or below, morepreferably to 33° C. or below. In certain methods, the administration ofthe liquid may be continued to provide for systemic cooling as well ascerebral cooling. In certain methods, the liquid may be cooled to belowbody temperature before delivery. The mist droplets may range in sizefrom 1-5 microns.

The table in FIG. 37 lists the parameters and results for cerebralcooling trials where the perfluorocarbon mixture used and the flow rateat which it was provided were varied. The column entitled “PFC” liststhe perfluorocarbon used and the column entitled “PFC flow mL/min” liststhe flow rate at which the PFC was administered. As seen from the“Cooling Rate” data, the faster the rate of administration of PFC, thegreater the cooling. The gas flow rate is listed in the column entitled“O₂ Flow L/min;” the greater the gas flow rate, the greater the cooling.In this experiment, the gas joined the liquid in a box and generated aspray. The spray was then delivered to the nasal cavity. Possible nasaltrauma limited the speed of delivery; for example, nasal bleeding may berate limiting. The ratio between the gas and the liquid was varied(e.g., 1:1, 1:2, 1:3) with varying effect on cooling rates. The columnentitled “BIAS flow” is CPAP (continuous positive airway pressure) airunder several atmospheres of pressure to enhance spray entry duringinspiration. Cooling was measured in Head-F (frontal lobe of the brain),Head V (ventricle of the brain), Head-S (superficial, cortical, andposterior portions of the brain), Vasc (vascular column), and Rectal(rectal column). Systemic column was measured in the vascular column.From the measurements it appears that Head F cools first and thefastest. Subsequently, the cold diffuses back to the ventricle and thento surface. A gradient is created within the brain and between brain andblood, such that brain cooling is more marked early on (20-30 degrees inone hour) than blood (10 degrees in one hour), systemic cooling, orrectal cooling. This gradient eventually disappears.

FIG. 38 shows a plot of brain temperatures against time for differentruns listed in FIG. 37. Table 1 (below) shows additional experimentaldata wherein the cooling liquid and the flow rate were varied.

TABLE 1 TIME 1:HEAD-F 1:HEAD-V HEAD-S 1:ESOPH 1:IM 1:SUBQ 1:RECTAL12:26:52 37.7 38.1 38.5 36.8 38.5 36.7 38.4 12:26:56 37.7 38.1 38.5 36.738.5 36.7 38.4 12:27:01 37.7 38.1 38.5 36.5 38.4 36.7 38.4 12:27:05 37.738.1 38.5 35.8 38.4 36.7 38.4 12:27:09 37.7 38.1 38.5 35.2 38.4 36.738.3 12:27:13 37.6 38.1 38.5 35 38.4 36.7 38.4 12:27:17 37.6 38 38.434.6 38.4 36.7 38.3 12:27:21 37.6 37.9 38.4 34.2 38.4 36.7 38.3 12:27:2637.5 37.8 38.4 34 38.4 36.7 38.4 12:27:30 37.4 37.8 38.5 33.3 38.5 36.738.4 12:27:34 37.3 37.7 38.5 33.1 38.4 36.7 38.3 12:27:38 37.3 37.7 38.432.9 38.4 36.7 38.3 12:27:42 37.2 37.6 38.4 32.8 38.3 36.7 38.3 12:27:4637.1 37.6 38.4 32.5 38.3 36.7 38.3 12:27:50 37.1 37.5 38.3 32.5 38.436.7 38.4 12:27:55 37 37.5 38.3 32.3 38.4 36.7 38.3 12:27:59 36.9 37.438.3 32.2 38.4 36.7 38.3 12:28:03 36.9 37.4 38.3 32.2 38.4 36.7 38.312:28:07 36.8 37.4 38.3 32.2 38.5 36.7 38.3 12:28:11 36.7 37.3 38.3 32.138.4 36.7 38.4 12:28:15 36.7 37.3 38.3 31.8 38.4 36.7 38.3 12:28:20 36.737.3 38.3 31.7 38.4 36.7 38.4 12:28:24 36.6 37.2 38.3 31.6 38.4 36.838.4 12:28:28 36.4 37.2 38.2 31.5 38.4 36.7 38.4 12:28:32 36.5 37.2 38.331.3 38.5 36.7 38.3 12:28:36 36.5 37.1 38.2 31.2 38.4 36.7 38.4 12:28:4036.5 37.1 38.2 31.1 38.4 36.7 38.3 12:28:44 36.4 37.1 38.2 31.1 38.436.8 38.4 12:28:49 36.3 37.1 38.2 31 38.4 36.7 38.3 12:28:53 36.3 3738.1 30.9 38.4 36.7 38.3 12:28:57 36.2 37 38.1 30.9 38.4 36.7 38.412:29:01 36.2 37 38.1 30.8 38.4 36.7 38.3 12:29:05 36.2 37 38.1 30.738.4 36.7 38.3 12:29:09 36.1 36.9 38.1 29.9 38.4 36.7 38.3 12:29:13 36.136.9 38.1 29.8 38.4 36.7 38.3 12:29:18 36.1 37 38.1 30 38.4 36.7 38.312:29:22 36 37 38.1 30.1 38.4 36.7 38.3 12:29:26 36.1 37 38.1 30.5 38.436.7 38.3 12:29:30 36 37 38 30.5 38.4 36.7 38.3 12:29:34 36 37 38 30.538.5 36.7 38.3 12:29:38 36 36.9 38 30.6 38.4 36.7 38.3 12:29:43 36 36.938 30.6 38.4 36.7 38.3 12:29:47 35.9 36.8 38 30.2 38.4 36.7 38.312:29:51 35.9 36.8 38 30.3 38.4 36.7 38.3 12:29:55 35.9 36.8 38 30.238.4 36.7 38.3 12:29:59 35.8 36.8 37.9 30.3 38.4 36.7 38.3 12:30:03 35.836.8 38 30.3 38.4 36.7 38.3 12:30:07 35.8 36.7 37.9 30.5 38.4 36.7 38.312:30:12 35.7 36.7 37.8 30.5 38.4 36.7 38.3 12:30:16 35.7 36.7 37.9 30.638.5 36.7 38.3 12:30:20 35.7 36.7 37.8 30.6 38.4 36.7 38.3 12:30:24 35.736.6 37.8 30.6 38.4 36.7 38.3 12:30:28 35.6 36.6 37.8 30.5 38.4 36.738.3 12:30:32 35.6 36.6 37.8 30.2 38.4 36.7 38.3  2:30:36 35.6 36.6 37.830.5 38.4 36.7 38.3 12:30:41 35.6 36.6 37.7 30.5 38.4 36.7 38.3 12:30:4535.5 36.5 37.7 30.3 38.4 36.7 38.2 12:30:49 35.5 36.5 37.7 30.2 38.436.7 38.3 12:30:53 35.5 36.5 37.7 30.2 38.4 36.7 38.3 12:30:57 35.5 36.537.7 30.1 38.4 36.7 38.2 12:31:01 35.3 36.4 37.6 30.2 38.3 36.6 38.212:31:06 35.3 36.4 37.6 30.1 38.4 36.7 38.2 12:31:10 35.3 36.5 37.6 30.138.4 36.7 38.2 12:31:14 35.3 36.5 37.6 30 38.4 36.6 38.2 12:31:18 35.336.5 37.6 30.1 38.4 36.7 38.3 12:31:22 35.2 36.4 37.6 30.2 38.4 36.738.2 12:31:26 35.2 36.4 37.6 30.2 38.4 36.7 38.2 12:31:30 35.2 36.3 37.630.2 38.4 36.7 38.2 12:31:35 35.1 36.3 37.5 30.1 38.4 36.6 38.2 12:31:3935.1 36.3 37.5 30.1 38.3 36.6 38.2 12:31:43 35.1 36.3 37.5 30.2 38.436.7 38.2 12:31:47 35.1 36.3 37.5 30.1 38.4 36.6 38.2 12:31:51 35.1 36.337.5 30.1 38.3 36.7 38.2 12:31:55 35.1 36.3 37.4 30.2 38.4 36.6 38.212:31:59 35.1 36.3 37.5 30.2 38.3 36.6 38.2 12:32:04 35 36.2 37.4 30.138.4 36.6 38.2 12:32:08 35 36.2 37.4 30.1 38.4 36.6 38.2 12:32:12 3536.2 37.4 30.1 38.4 36.6 38.2 12:32:16 34.9 36.2 37.4 30.1 38.4 36.638.2 12:32:20 34.9 36.2 37.4 30.1 38.4 36.6 38.2 12:32:24 34.9 36.1 37.330.1 38.4 36.6 38.2 12:32:29 34.8 36.1 37.3 30.1 38.4 36.6 38.2 12:32:3334.8 36.1 37.3 30 38.4 36.7 38.2 12:32:37 34.8 36.1 37.3 30 38.3 36.638.1 12:32:41 34.8 36.1 37.2 29.8 38.3 36.6 38.1 12:32:45 34.8 36.1 37.229.8 38.3 36.6 38.2 12:32:49 34.8 36 37.2 29.8 38.4 36.6 38.2 12:32:5334.7 36 37.2 29.8 38.4 36.6 38.2 12:32:58 34.7 36 37.2 29.8 38.3 36.638.2 12:33:02 34.7 36 37.1 29.8 38.3 36.6 38.1 12:33:06 34.7 36 37.129.5 38.3 36.6 38.1 12:33:10 34.7 36 37.1 29.5 38.3 36.6 38.1 12:33:1434.7 36 37.1 29.5 38.3 36.6 38.2 12:33:18 34.6 35.9 37.1 29.5 38.3 36.638.1 12:33:23 34.6 36 37.1 29.5 38.4 36.6 38.1 12:33:27 34.6 36 37.129.5 38.4 36.6 38.1 12:33:31 34.6 35.9 37.1 29.5 38.3 36.6 38.1 12:33:3534.6 35.9 37.1 29.4 38.3 36.6 38.1 12:33:39 34.6 35.9 37 29.3 38.3 36.638.1 12:33:43 34.6 36 37 29.4 38.4 36.6 38.1 12:33:47 34.6 36 37 29.338.3 36.6 38.1 12:33:52 34.6 36 37 29.3 38.3 36.6 38.1 12:33:56 34.6 3637 29.2 38.3 36.6 38.1 12:34:00 34.7 36 37 29.2 38.3 36.6 38.1 12:34:0434.7 36 37 29.2 38.4 36.7 38.2 12:34:08 34.6 36 37 29.1 38.3 36.6 38.112:34:12 34.6 36 37 29.2 38.3 36.6 38.1 12:34:16 34.6 36 37 29.1 38.336.6 38.1 12:34:21 34.6 36 36.9 29.1 38.3 36.6 38.1 12:34:25 34.6 3636.9 29 38.3 36.6 38.1 12:34:29 34.6 35.9 37 29 38.4 36.6 38.1 12:34:3334.5 35.9 36.9 29 38.3 36.6 38.1 12:34:37 34.5 35.9 36.9 28.9 38.3 36.638.1 12:34:41 34.5 35.9 36.9 28.9 38.3 36.6 38.1 12:34:46 34.5 35.9 36.928.9 38.3 36.6 38.1 12:34:50 34.5 35.8 36.8 28.8 38.3 36.6 38.1 12:34:5434.5 35.8 36.8 28.8 38.3 36.6 38.1 12:34:58 34.5 35.8 36.8 29 38.3 36.638.1 12:35:02 34.4 35.8 36.8 29.1 38.3 36.6 38.1 12:35:06 34.5 35.8 36.829.1 38.3 36.6 38.1 12:35:11 34.4 35.7 36.8 29 38.3 36.5 38.1 12:35:1534.3 35.7 36.8 29 38.3 36.6 38 12:35:19 34.3 35.7 36.8 29 38.3 36.6 38.112:35:23 34.2 35.6 36.7 28.9 38.3 36.6 38 12:35:27 34.2 35.6 36.7 2938.3 36.5 38 12:35:31 34.2 35.6 36.7 29.1 38.3 36.5 38 12:35:35 34.235.7 36.7 29.1 38.3 36.5 38 12:35:40 34.2 35.7 36.7 29.1 38.3 36.5 38.112:35:44 34.2 35.7 36.7 29.2 38.3 36.5 38 12:35:48 34.2 35.6 36.7 29.238.3 36.5 38 12:35:52 34.2 35.6 36.6 29.2 38.3 36.5 38 12:35:56 34.135.5 36.6 29.2 38.3 36.5 38 12:36:00 34.1 35.6 36.7 29.1 38.3 36.5 3812:36:04 34.1 35.5 36.6 29.2 38.3 36.5 38.1 12:36:09 34.1 35.5 36.6 29.238.3 36.5 38 12:36:13 34.1 35.5 36.6 29.2 38.3 36.5 38 12:36:17 34 35.536.6 29.2 38.3 36.5 38 12:36:21 34 35.5 36.6 29.2 38.3 36.5 38 12:36:2534 35.5 36.6 29.3 38.3 36.5 37.9 12:36:29 34 35.5 36.5 28.9 38.3 36.5 3812:36:34 34 35.5 36.5 29 38.3 36.5 38 12:36:38 34 35.5 36.5 29.1 38.336.5 38 12:36:42 33.9 35.4 36.5 29.1 38.3 36.5 38 12:36:46 33.9 35.436.5 29.2 38.3 36.5 38 12:36:50 33.9 35.3 36.5 29.2 38.3 36.5 3812:36:54 33.8 35.4 36.5 29.2 38.3 36.5 38 12:36:58 33.8 35.3 36.5 29.238.2 36.5 38 12:37:03 33.8 35.4 36.5 29.2 38.3 36.5 38 12:37:07 33.835.3 36.5 29.2 38.3 36.4 38 12:37:11 33.8 35.3 36.5 29.2 38.3 36.5 3812:37:15 33.8 35.3 36.4 29.2 38.2 36.4 37.9 12:37:19 33.8 35.3 36.5 29.338.3 36.5 38 12:37:23 33.8 35.3 36.4 29.2 38.3 36.5 38 12:37:28 33.835.3 36.4 29.2 38.2 36.5 37.9 12:37:32 33.8 35.3 36.4 29.2 38.2 36.437.9 12:37:36 33.7 35.2 36.3 29.2 38.2 36.4 37.9 12:37:40 33.7 35.2 36.429.2 38.2 36.4 38 12:37:44 33.7 35.2 36.4 29.2 38.2 36.5 38 12:37:4833.7 35.2 36.3 29.2 38.2 36.4 37.9 12:37:53 33.7 35.2 36.3 28.7 38.336.4 37.9 12:37:57 33.7 35.2 36.3 28.7 38.2 36.4 37.9 12:38:01 33.7 35.236.3 28.7 38.3 36.5 37.9 12:38:05 33.7 35.2 36.3 28.7 38.3 36.5 3812:38:09 33.6 35.2 36.3 28.6 38.2 36.4 37.9 12:38:13 33.6 35.2 36.3 28.638.2 36.4 37.9 12:38:17 33.6 35.2 36.2 28.6 38.2 36.4 37.8 12:38:21 33.635.2 36.3 28.6 38.2 36.5 37.9 12:38:25 33.6 35.2 36.3 28.6 38.3 36.537.9 12:38:30 33.6 35.1 36.2 28.5 38.2 36.4 37.8 12:38:34 33.6 35.2 36.228.5 38.3 36.4 37.9 12:38:38 33.6 35.1 36.2 28.5 38.2 36.4 37.8 12:38:4233.6 35.1 36.1 28.4 38.2 36.3 37.8 12:38:46 33.6 35.1 36.2 28.3 38.236.4 37.8 12:38:50 33.6 35.1 36.2 28.4 38.2 36.5 37.9 12:38:55 33.6 35.136.2 28.3 38.2 36.4 37.9 12:38:59 33.6 35.1 36.1 28.4 38.2 36.4 37.812:39:03 33.6 35.1 36.2 28.3 38.2 36.4 37.8 12:39:07 33.5 35.1 36.1 28.338.2 36.3 37.8 12:39:11 33.6 35.1 36.1 28.3 38.2 36.3 37.8 12:39:15 33.635.1 36.1 28.3 38.2 36.4 37.8 12:39:19 33.6 35.1 36.1 28.3 38.2 36.437.8 12:39:24 33.5 35.1 36.1 28.2 38.2 36.3 37.8 12:39:28 33.6 35.1 36.128.2 38.2 36.4 37.8 12:39:32 33.5 35.1 36.1 28.1 38.2 36.3 37.8 12:39:3633.6 35.1 36.1 28.2 38.2 36.4 37.8 12:39:40 33.5 35 36.1 28.1 38.2 36.337.8 12:39:44 33.6 35 36 28.1 38.2 36.3 37.8 12:39:49 33.6 35 36 28.138.2 36.3 37.8 12:39:53 33.5 35 36 28.1 38.2 36.3 37.8 12:39:57 33.5 3536 28 38.2 36.3 37.8 12:40:01 33.5 35 36 28 38.2 36.3 37.8 12:40:05 33.535 36 27.9 38.2 36.3 37.8 12:40:09 33.5 35 36 28 38.2 36.3 37.8 12:40:1333.5 35 36 27.9 38.2 36.3 37.8 12:40:18 33.5 35 36 27.9 38.2 36.3 37.812:40:22 33.5 35 36 27.9 38.2 36.3 37.8 12:40:26 33.5 35 36 27.9 38.236.3 37.8 12:40:30 33.5 35 36 27.9 38.2 36.3 37.7 12:40:34 33.5 35 3627.9 38.2 36.3 37.7 12:40:38 33.5 35 35.9 27.8 38.2 36.3 37.7 12:40:4233.5 35 36 27.8 38.2 36.3 37.7 12:40:47 33.5 35 35.9 27.8 38.1 36.3 37.812:40:51 33.5 35 36 27.7 38.2 36.3 37.7 12:40:55 33.6 34.9 35.9 27.838.2 36.3 37.8 12:40:59 33.5 34.9 35.9 27.8 38.2 36.3 37.7 12:41:03 33.534.9 35.9 27.7 38.2 36.3 37.7 12:41:07 33.5 34.9 35.9 27.8 38.2 36.337.7 12:41:12 33.6 34.9 35.9 27.7 38.2 36.3 37.7 12:41:16 33.5 34.9 35.927.7 38.2 36.3 37.7 12:41:20 33.5 34.9 35.9 27.6 38.2 36.3 37.7 12:41:2433.6 34.9 35.8 27.6 38.1 36.3 37.7 12:41:28 33.5 34.9 35.8 27.6 38.136.3 37.7 12:41:32 33.6 34.9 35.8 27.6 38.1 36.3 37.7 12:41:36 33.5 34.835.8 27.6 38.1 36.2 37.7 12:41:41 33.6 34.9 35.8 27.6 38.1 36.3 37.712:41:45 33.5 34.8 35.8 27.7 38.1 36.2 37.7 12:41:49 33.6 34.8 35.8 27.738.1 36.3 37.7 12:41:53 33.6 34.8 35.8 27.8 38.1 36.3 37.7 12:41:57 33.634.9 35.8 28 38.1 36.3 37.7 12:42:01 33.6 35 35.8 28 38.1 36.3 37.712:42:05 33.7 35 35.7 28.6 38.1 36.3 37.7 12:42:10 33.7 35 35.8 28.338.1 36.3 37.7 12:42:14 33.7 35 35.7 28.2 38.1 36.2 37.7 12:42:18 33.835.1 35.8 28 38.1 36.2 37.7 12:42:22 33.8 35.1 35.8 27.8 38.1 36.3 37.712:42:26 33.9 35.1 35.7 27.7 38.1 36.3 37.7 12:42:30 33.9 35.1 35.7 27.638.1 36.2 37.7 12:42:35 34 35.1 35.8 27.6 38.1 36.3 37.7 12:42:39 3435.1 35.7 27.5 38.1 36.3 37.7 12:42:43 34 35.1 35.8 27.5 38.1 36.3 37.712:42:47 34 35.1 35.7 27.4 38.1 36.3 37.7 12:42:51 34 35.1 35.7 27.338.1 36.2 37.7 12:42:55 34 35.1 35.7 27.2 38.1 36.3 37.7 12:42:59 34.135.1 35.8 27.2 38.1 36.3 37.7 12:43:04 34.1 35.1 35.8 27.2 38.1 36.337.7 12:43:08 34 35.1 35.7 27.2 38.1 36.2 37.6 12:43:12 34.1 35.1 35.727.3 38 36.2 37.6 12:43:16 34.1 35.1 35.7 27.5 38.1 36.2 37.6 12:43:2034.2 35.2 35.7 27.5 38.1 36.2 37.6 12:43:24 34.3 35.3 35.7 27.6 38.136.2 37.6 12:43:28 34.3 35.5 35.7 27.6 38.1 36.2 37.6 12:43:33 34.4 35.535.7 27.5 38.1 36.2 37.6 12:43:37 34.5 35.5 35.7 27.5 38.1 36.2 37.612:43:41 34.7 35.5 35.7 27.4 38.1 36.2 37.6 12:43:45 34.7 35.5 35.8 27.438.1 36.2 37.6 12:43:49 34.7 35.5 35.8 27.4 38.1 36.2 37.6 12:43:53 34.735.5 35.8 27.3 38 36.2 37.6 12:43:58 34.7 35.4 35.7 27.4 38.1 36.2 37.612:44:02 34.8 35.5 35.8 27.4 38.1 36.2 37.6 12:44:06 34.8 35.6 35.8 27.538.1 36.2 37.6 12:44:10 34.8 35.6 35.8 27.5 38 36.2 37.6 12:44:14 34.935.6 35.8 27.5 38 36.2 37.6 12:44:18 35 35.6 35.8 27.5 38 36.2 37.612:44:22 35 35.6 35.8 27.6 38 36.2 37.6 12:44:27 35.1 35.7 35.8 27.738.1 36.2 37.6 12:44:31 35.1 35.6 35.8 27.7 38 36.2 37.6 12:44:35 35.135.7 35.8 27.7 38 36.2 37.6 12:44:39 35.1 35.6 35.8 27.7 38 36.2 37.512:44:43 35.1 35.6 35.9 27.8 38.1 36.2 37.5 12:44:47 35.1 35.6 35.9 27.838 36.2 37.6 12:44:52 35.1 35.6 35.8 27.7 38 36.2 37.6 12:44:56 35.135.7 35.8 27.6 38 36.1 37.5 12:45:00 35.1 35.7 35.8 27.6 38 36.2 37.612:45:04 35.2 35.7 35.9 27.5 38 36.2 37.6 12:45:08 35.2 35.7 35.9 27.638 36.2 37.6 12:45:12 35.2 35.8 35.8 27.5 38 36.2 37.6 12:45:17 35.235.8 35.8 27.5 38 36.2 37.5 12:45:21 35.2 35.8 35.9 27.5 38 36.1 37.612:45:25 35.3 35.8 35.9 27.5 38 36.1 37.6 12:45:29 35.3 35.8 35.9 27.538 36.1 37.5 12:45:33 35.3 35.8 35.9 27.5 38 36.2 37.6 12:45:37 35.335.8 36 27.5 38 36.2 37.6 12:45:41 35.3 35.7 35.9 27.5 38 36.1 37.512:45:46 35.2 35.7 35.9 27.6 38 36.1 37.5 12:45:50 35.2 35.7 36 27.6 3836.1 37.6 12:45:54 35.2 35.7 35.9 27.6 38 36.1 37.5 12:45:58 35.2 35.736 27.6 38 36.1 37.5 12:46:02 35.3 35.8 35.9 27.6 38 36.1 37.5 12:46:0635.3 35.8 36 27.6 38 36.1 37.5 12:46:10 35.3 35.8 36 27.6 38 36.2 37.512:46:15 35.3 35.8 35.9 27.6 38 36.1 37.5 12:46:19 35.3 35.9 36 27.8 3836.1 37.5 12:46:23 35.3 35.9 36 27.7 38 36.1 37.5 12:46:27 35.4 35.9 3627.7 38 36.2 37.6 12:46:31 35.4 35.9 36 27.6 38 36.1 37.5 12:46:35 35.535.9 36 27.5 38 36.1 37.5 12:46:40 35.5 35.9 36 27.5 38 36.1 37.512:46:44 35.5 35.9 36 27.5 38 36.1 37.5 12:46:48 35.5 35.9 36 27.5 3836.1 37.5 12:46:52 35.5 36 36 27.5 38 36.1 37.5 12:46:56 35.5 35.9 3627.5 38 36.1 37.5 12:47:00 35.5 36 36 27.4 38 36.1 37.4 12:47:04 35.535.9 36 27.3 38 36.1 37.5 12:47:08 35.5 35.9 36 27.3 38 36.1 37.512:47:13 35.5 35.9 36 27.2 38 36.1 37.5 12:47:17 35.5 35.9 36.1 27.1 3836.1 37.5 12:47:21 35.5 35.9 36.1 27.1 38 36.1 37.4 12:47:25 35.5 35.936 27.1 38 36.1 37.5 12:47:29 35.5 36 36.1 27.1 38 36.1 37.4 12:47:3335.5 35.9 36 27.1 38 36.1 37.4 12:47:37 35.5 36 36.1 27 38 36 37.412:47:42 35.5 36 36 27 38 36.1 37.4 12:47:46 35.5 36 36.1 27 38 36 37.412:47:50 35.5 35.9 36 27 38 36.1 37.5 12:47:54 35.5 36 36 26.8 38 3637.4 12:47:58 35.6 36 36.1 26.9 38 36 37.4 12:48:02 35.6 36 36.1 26.8 3836.1 37.4 12:48:07 35.6 36 36.1 26.9 37.9 36 37.4 12:48:11 35.6 36 36.126.9 38 36 37.4 12:48:15 35.6 36 36.1 26.9 38 36 37.4 12:48:19 35.5 3636 26.9 37.9 36 37.3 12:48:23 35.5 35.9 36.1 26.9 38 36 37.3 12:48:2735.5 36 36.1 26.9 38 36 37.4 12:48:32 35.5 36 36.1 27.2 37.9 36 37.412:48:36 35.5 36 36.1 27.3 38 36.1 37.4 12:48:40 35.5 35.9 36.1 27.137.9 36 37.3 12:48:44 35.5 36 36.1 27.2 38 36 37.4 12:48:48 35.5 36 36.127.5 37.9 36 37.3 12:48:52 35.5 36 36.1 27.5 38 36 37.4 12:48:56 35.535.9 36.1 27.5 37.9 36 37.3 12:49:00 35.5 36 36.1 27.6 37.9 36 37.312:49:05 35.5 35.9 36.1 27.4 37.9 36 37.3 12:49:09 35.5 36 36.1 27.137.9 36 37.3 12:49:13 35.5 35.9 36.1 27 38 36 37.3 12:49:17 35.5 35.936.1 26.8 37.9 36 37.3 12:49:21 35.4 35.9 36.1 26.8 37.9 36 37.312:49:25 35.4 35.9 36.1 26.8 37.9 36 37.3 12:49:30 35.4 35.8 36.1 26.837.9 36 37.3 12:49:34 35.3 35.8 36.1 26.7 37.9 36 37.3 12:49:38 35.335.8 36.1 26.6 37.9 36 37.3 12:49:42 35.3 35.8 36.1 26.5 37.9 36 37.312:49:46 35.3 35.8 36.1 26.3 37.9 36 37.3 12:49:50 35.3 35.8 36.1 26.237.9 36 37.3 12:49:55 35.3 35.8 36.1 26.1 37.9 36 37.3 12:49:59 35.335.8 36.1 25.9 37.9 36 37.3 12:50:03 35.2 35.8 36.1 25.9 37.9 36 37.312:50:07 35.2 35.8 36.1 26 37.9 36 37.3 12:50:11 35.2 35.8 36.1 26 37.936 37.3 12:50:15 35.2 35.7 36.1 25.8 37.9 36 37.3 12:50:20 35.1 35.736.1 25.7 37.9 36 37.3 12:50:24 35.1 35.7 36.1 25.7 37.9 35.9 37.212:50:28 35.1 35.7 36.1 25.7 37.8 36 37.3 12:50:32 35.1 35.7 36.1 25.637.8 35.9 37.3 12:50:36 35.1 35.7 36.1 25.6 37.8 35.9 37.2 12:50:40 35.135.7 36.1 25.7 37.9 36 37.3 12:50:44 35 35.7 36.1 25.6 37.9 36 37.312:50:49 35 35.6 36.1 25.7 37.9 36 37.2 12:50:53 35 35.6 36 25.7 37.835.9 37.2 12:50:57 35 35.6 36 25.6 37.8 35.9 37.2 12:51:01 34.9 35.6 3625.7 37.8 35.9 37.2 12:51:05 34.9 35.6 36 25.7 37.8 35.6 37.2 12:51:1034.8 35.6 36 25.7 37.8 35.9 37.2 12:51:14 34.8 35.6 36 25.7 37.8 35.937.2 12:51:18 34.8 35.6 36.1 25.7 37.9 35.9 37.2 12:51:22 34.8 35.6 3625.7 37.8 36 37.3 12:51:26 34.8 35.5 36 25.6 37.8 35.9 37.3 12:51:3034.8 35.5 36 25.5 37.8 35.9 37.2 12:51:34 34.8 35.5 36 25.5 37.8 35.937.2 12:51:39 34.7 35.5 36 25.5 37.8 35.9 37.2 12:51:43 34.7 35.5 3625.6 37.8 35.9 37.2 12:51:47 34.7 35.5 36 25.6 37.8 35.9 37.2 12:51:5134.7 35.5 36 25.6 37.8 35.8 37.2 12:51:55 34.7 35.5 36 25.6 37.8 35.937.2 12:51:59 34.7 35.5 36 25.6 37.8 35.8 37.2 12:52:04 34.7 35.5 3625.6 37.8 35.9 37.2 12:52:08 34.7 35.5 36 25.6 37.8 35.9 37.2 12:52:1234.7 35.5 36 25.6 37.8 35.8 37.2 12:52:16 34.7 35.4 36 25.6 37.8 35.937.2 12:52:20 34.7 35.4 36 25.5 37.8 35.8 37.2 12:52:24 34.7 35.4 3625.5 37.8 35.8 37.2 12:52:28 34.6 35.5 36 25.5 37.8 35.8 37.2 12:52:3234.6 35.4 35.9 25.5 37.8 35.9 37.2 12:52:37 34.6 35.4 35.9 25.5 37.835.8 37.2 12:52:41 34.6 35.4 35.9 25.5 37.8 35.8 37.2 12:52:45 34.6 35.335.9 25.5 37.8 35.8 37.2 12:52:49 34.6 35.4 35.9 25.5 37.8 35.9 37.212:52:53 34.6 35.4 35.9 25.5 37.8 35.8 37.1 12:52:58 34.6 35.3 35.9 25.437.8 35.8 37.2 12:53:02 34.6 35.3 35.9 25.6 37.8 35.8 37.2 12:53:06 34.635.3 35.9 25.5 37.8 35.8 37.1 12:53:10 34.6 35.4 35.9 25.5 37.8 35.837.1 12:53:14 34.6 35.3 35.9 25.5 37.8 35.8 37.2 12:53:18 34.6 35.3 35.925.6 37.8 35.8 37.2 12:53:22 34.6 35.3 35.8 25.6 37.8 35.8 37.2 12:53:2734.6 35.3 35.9 25.6 37.8 35.8 37.2 12:53:31 34.6 35.3 35.9 25.7 37.835.8 37.2 12:53:35 34.6 35.3 35.8 25.7 37.8 35.8 37.1 12:53:39 34.6 35.335.9 25.6 37.8 35.8 37.2 12:53:43 34.6 35.3 35.8 25.6 37.8 35.8 37.212:53:47 34.6 35.3 35.8 25.6 37.8 35.8 37.1 12:53:51 34.6 35.3 35.8 25.637.8 35.8 37.1 12:53:55 34.6 35.3 35.8 25.5 37.8 35.8 37.1 12:54:00 34.635.3 35.8 25.6 37.8 35.8 37.2 12:54:04 34.6 35.3 35.8 25.5 37.8 35.837.2 12:54:08 34.6 35.3 35.8 25.4 37.7 35.8 37.1 12:54:12 34.6 35.3 35.825.5 37.8 35.8 37.1 12:54:16 34.6 35.3 35.8 25.4 37.8 35.8 37.1 12:54:2034.6 35.3 35.8 25.4 37.7 35.8 37.1 12:54:24 34.6 35.3 35.8 25.4 37.835.8 37.1 12:54:29 34.6 35.3 35.8 25.5 37.7 35.8 37.1 12:54:33 34.6 35.435.7 25.5 37.7 35.8 37.1 12:54:37 34.7 35.3 35.8 25.6 37.7 35.8 37.112:54:41 34.6 35.3 35.8 26 37.7 35.8 37.1 TIME 1:VASC 1:AIRWAY 1:EARMINUTES HEAD-M COOLING NOSE 12:26:52 37.7 30.3 32.3 0 38.1 0 26.612:26:56 37.7 30 32.3 0.066667 38.1 0 27.9 12:27:01 37.6 29.6 32.2 0.1538.1 0 27 12:27:05 37.6 29.1 32.2 0.216667 38.1 0 15 12:27:09 37.6 28.932.3 0.283333 38.1 0 14 12:27:13 37.5 29.3 32.3 0.35 38.06667 −0.0333312.8 12:27:17 37.3 29.8 32.3 0.416667 38 −0.1 12.9 12:27:21 37.3 30.132.3 0.483333 37.96667 −0.13333 12.6 12:27:26 37.1 29.7 32.3 0.56666737.9 −0.2 11.8 12:27:30 37.1 29.4 32.3 0.633333 37.9 −0.2 12 12:27:34 3729 32.3 0.7 37.83333 −0.26667 11.7 12:27:38 36.9 28.9 32.3 0.766667 37.8−0.3 12 12:27:42 36.8 29.2 32.3 0.833333 37.73333 −0.36667 11.5 12:27:4636.7 29.7 32.3 0.9 37.7 −0.4 11.7 12:27:50 36.7 29.7 32.3 0.96666737.63333 −0.46667 11.8 12:27:55 36.7 29.6 32.3 1.05 37.6 −0.5 11.712:27:59 36.7 29.2 32.3 1.116667 37.53333 −0.56667 11.4 12:28:03 36.628.8 32.2 1.183333 37.53333 −0.56667 11.2 12:28:07 36.6 28.8 32.3 1.2537.5 −0.6 11 12:28:11 36.5 29 32.3 1.316667 37.43333 −0.66667 10.812:28:15 36.6 29.5 32.3 1.383333 37.43333 −0.66667 10.8 12:28:20 36.729.8 32.3 1.466667 37.43333 −0.66667 11 12:28:24 36.8 29.6 32.3 1.53333337.36667 −0.73333 11.2 12:28:28 36.9 29.3 32.3 1.6 37.26667 −0.8333311.1 12:28:32 36.8 28.8 32.3 1.666667 37.33333 −0.76667 11.1 12:28:3636.8 28.7 32.3 1.733333 37.26667 −0.83333 11.2 12:28:40 36.8 29 32.3 1.837.26667 −0.83333 11.1 12:28:44 36.7 29.5 32.3 1.866667 37.23333−0.86667 11 12:28:49 36.8 29.9 32.3 1.95 37.2 −0.9 11.2 12:28:53 37 29.632.3 2.016667 37.13333 −0.96667 11.2 12:28:57 36.8 29.2 32.3 2.08333337.1 −1 11.1 12:29:01 36.8 28.8 32.3 2.15 37.1 −1 11.2 12:29:05 36.829.2 32.3 2.216667 37.1 −1 11.2 12:29:09 36.8 29.2 32.3 2.28333337.03333 −1.06667 11.3 12:29:13 36.6 29.6 32.3 2.35 37.03333 −1.0666710.8 12:29:18 36.5 29.2 32.2 2.433333 37.06667 −1.03333 10.9 12:29:2236.7 28.7 32.3 2.5 37.03333 −1.06667 10.5 12:29:26 36.5 28.5 32.32.566667 37.06667 −1.03333 10.8 12:29:30 36.6 28.6 32.3 2.633333 37 −1.110.8 12:29:34 36.5 29 32.3 2.7 37 −1.1 11 12:29:38 36.5 29.3 32.32.766667 36.96667 −1.13333 10.9 12:29:43 36.4 29.5 32.3 2.85 36.96667−1.13333 10.9 12:29:47 36.5 29.2 32.3 2.916667 36.9 −1.2 10.8 12:29:5136.7 28.8 32.3 2.983333 36.9 −1.2 10.9 12:29:55 36.7 28.5 32.3 3.05 36.9−1.2 10.8 12:29:59 36.7 28.5 32.3 3.116667 36.83333 −1.26667 10.812:30:03 36.7 29 32.3 3.183333 36.86667 −1.23333 11.1 12:30:07 36.7 29.532.3 3.25 36.8 −1.3 10.9 12:30:12 36.7 29.4 32.3 3.333333 36.73333−1.36667 10.9 12:30:16 36.7 29.1 32.3 3.4 36.76667 −1.33333 11 12:30:2036.7 28.7 32.3 3.466667 36.73333 −1.36667 11.1 12:30:24 36.7 28.5 32.33.533333 36.7 −1.4 10.9 12:30:28 36.7 28.9 32.3 3.6 36.66667 −1.43333 1112:30:32 36.6 29.4 32.3 3.666667 36.66667 −1.43333 11.1  2:30:36 36.729.5 32.3 3.733333 36.66667 −1.43333 11.1 12:30:41 36.7 29.1 32.33.816667 36.63333 −1.46667 10.8 12:30:45 36.7 28.7 32.3 3.88333336.56667 −1.53333 11 12:30:49 36.7 28.4 32.3 3.95 36.56667 −1.53333 11.112:30:53 36.6 28.6 32.3 4.016667 36.56667 −1.53333 11 12:30:57 36.6 29.232.3 4.083333 36.56667 −1.53333 11 12:31:01 36.7 29.4 32.2 4.15 36.43333−1.66667 11 12:31:06 36.7 29.2 32.3 4.233333 36.43333 −1.66667 1112:31:10 36.7 28.7 32.2 4.3 36.46667 −1.63333 10.8 12:31:14 36.6 28.332.3 4.366667 36.46667 −1.63333 11 12:31:18 36.6 28.3 32.3 4.43333336.46667 −1.63333 11 12:31:22 36.7 28.5 32.3 4.5 36.4 −1.7 11.1 12:31:2636.7 29.1 32.2 4.566667 36.4 −1.7 11 12:31:30 36.7 29.2 32.3 4.63333336.36667 −1.73333 11.3 12:31:35 36.6 28.9 32.2 4.716667 36.3 −1.8 11.312:31:39 36.7 28.5 32.2 4.783333 36.3 −1.8 11.2 12:31:43 36.7 28.2 32.24.85 36.3 −1.8 11.2 12:31:47 36.6 28.2 32.3 4.916667 36.3 −1.8 11.212:31:51 36.6 28.7 32.3 4.983333 36.3 −1.8 11 12:31:55 36.6 29.1 32.25.05 36.26667 −1.83333 10.9 12:31:59 36.5 29.1 32.2 5.116667 36.3 −1.811 12:32:04 36.6 28.7 32.2 5.2 36.2 −1.9 10.9 12:32:08 36.6 28.2 32.25.266667 36.2 −1.9 11 12:32:12 36.6 28 32.2 5.333333 36.2 −1.9 10.712:32:16 36.6 28.2 32.2 5.4 36.16667 −1.93333 11.3 12:32:20 36.6 28.732.2 5.466667 36.16667 −1.93333 11.1 12:32:24 36.6 29 32.2 5.533333 36.1−2 10.8 12:32:29 36.6 28.7 32.2 5.616667 36.06667 −2.03333 10.8 12:32:3336.5 28.3 32.2 5.683333 36.06667 −2.03333 10.7 12:32:37 36.6 28 32.25.75 36.06667 −2.03333 10.8 12:32:41 36.6 28 32.2 5.816667 36.03333−2.06667 10.8 12:32:45 36.6 28.2 32.2 5.883333 36.03333 −2.06667 1112:32:49 36.6 28.7 32.2 5.95 36 −2.1 11 12:32:53 36.6 28.9 32.2 6.01666735.96667 −2.13333 11 12:32:58 36.7 28.7 32.2 6.1 35.96667 −2.13333 10.812:33:02 36.6 28.2 32.2 6.166667 35.93333 −2.16667 10.9 12:33:06 36.628.1 32.2 6.233333 35.93333 −2.16667 10.8 12:33:10 36.5 28.5 32.2 6.335.93333 −2.16667 10.8 12:33:14 36.6 29 32.2 6.366667 35.93333 −2.1666710.6 12:33:18 36.6 29 32.2 6.433333 35.86667 −2.23333 10.9 12:33:23 36.728.8 32.2 6.516667 35.9 −2.2 10.8 12:33:27 36.7 28.4 32.2 6.583333 35.9−2.2 10.8 12:33:31 36.7 28 32.2 6.65 35.86667 −2.23333 10.8 12:33:3536.6 28.1 32.2 6.716667 35.86667 −2.23333 10.8 12:33:39 36.6 28.7 32.26.783333 35.83333 −2.26667 10.7 12:33:43 36.6 29 32.2 6.85 35.86667−2.23333 11.1 12:33:47 36.6 28.7 32.2 6.916667 35.86667 −2.23333 10.812:33:52 36.6 28.4 32.2 7 35.86667 −2.23333 10.6 12:33:56 36.6 28.1 32.27.066667 35.86667 −2.23333 10.6 12:34:00 36.6 28 32.2 7.133333 35.9 −2.210.7 12:34:04 36.6 28.2 32.2 7.2 35.9 −2.2 10.7 12:34:08 36.5 28.6 32.27.266667 35.86667 −2.23333 10.7 12:34:12 36.6 29 32.2 7.333333 35.86667−2.23333 10.7 12:34:16 36.5 28.8 32.2 7.4 35.86667 −2.23333 10.612:34:21 36.6 28.5 32.2 7.483333 35.83333 −2.26667 10.6 12:34:25 36.528.1 32.2 7.55 35.83333 −2.26667 10.4 12:34:29 36.5 28 32.2 7.61666735.83333 −2.26667 10.6 12:34:33 36.5 28.2 32.2 7.683333 35.76667−2.33333 10.6 12:34:37 36.4 28.6 32.2 7.75 35.76667 −2.33333 10.512:34:41 36.5 28.9 32.2 7.816667 35.76667 −2.33333 10.4 12:34:46 36.528.7 32.2 7.9 35.76667 −2.33333 10.5 12:34:50 36.5 28.4 32.2 7.96666735.7 −2.4 10.7 12:34:54 36.4 28.2 32.2 8.033333 35.7 −2.4 10.5 12:34:5836.3 27.9 32.2 8.1 35.7 −2.4 10.3 12:35:02 36.3 27.9 32.2 8.16666735.66667 −2.43333 10.3 12:35:06 36.3 28.2 32.2 8.233333 35.7 −2.4 10.312:35:11 36.3 28.6 32.2 8.316667 35.63333 −2.46667 10.3 12:35:15 36.328.6 32.1 8.383333 35.6 −2.5 10.2 12:35:19 36.4 28.3 32.2 8.45 35.6 −2.510.3 12:35:23 36.3 28 32.2 8.516667 35.5 −2.6 10.3 12:35:27 36.3 27.832.1 8.583333 35.5 −2.6 10.2 12:35:31 36.3 27.8 32.1 8.65 35.5 −2.6 10.212:35:35 36.3 28.1 32.1 8.716667 35.53333 −2.56667 10.1 12:35:40 36.328.5 32.2 8.8 35.53333 −2.56667 10.1 12:35:44 36.3 28.6 32.2 8.86666735.53333 −2.56667 9.9 12:35:48 36.4 28.5 32.2 8.933333 35.5 −2.6 1012:35:52 36.5 28.2 32.2 9 35.46667 −2.63333 10 12:35:56 36.4 28 32.29.066667 35.4 −2.7 9.9 12:36:00 36.4 27.7 32.1 9.133333 35.46667−2.63333 9.7 12:36:04 36.5 28.1 32.2 9.2 35.4 −2.7 9.9 12:36:09 36.428.4 32.2 9.283333 35.4 −2.7 9.8 12:36:13 36.3 28.6 32.1 9.35 35.4 −2.79.8 12:36:17 36.4 28.6 32.1 9.416667 35.36667 −2.73333 9.8 12:36:21 36.428.3 32.2 9.483333 35.36667 −2.73333 9.7 12:36:25 36.4 28 32.1 9.5535.36667 −2.73333 9.8 12:36:29 36.4 27.8 32.2 9.616667 35.33333 −2.766679.7 12:36:34 36.4 27.8 32.1 9.7 35.33333 −2.76667 9.6 12:36:38 36.3 27.932.1 9.766667 35.33333 −2.76667 9.7 12:36:42 36.4 28.3 32.1 9.83333335.26667 −2.83333 9.7 12:36:46 36.3 28.5 32.1 9.9 35.26667 −2.83333 9.612:36:50 36.3 28.3 32.1 9.966667 35.23333 −2.86667 9.5 12:36:54 36.328.1 32.1 10.03333 35.23333 −2.86667 9.6 12:36:58 36.3 27.8 32.1 10.135.2 −2.9 9.6 12:37:03 36.4 27.6 32.1 10.18333 35.23333 −2.86667 9.512:37:07 36.3 27.8 32.1 10.25 35.2 −2.9 9.5 12:37:11 36.3 28.2 32.110.31667 35.2 −2.9 9.6 12:37:15 36.3 28.2 32.1 10.38333 35.16667−2.93333 9.6 12:37:19 36.3 28.1 32.1 10.45 35.2 −2.9 9.4 12:37:23 36.327.8 32.1 10.51667 35.16667 −2.93333 9.6 12:37:28 36.3 27.6 32.1 10.635.16667 −2.93333 9.6 12:37:32 36.3 27.7 32.1 10.66667 35.16667 −2.933339.3 12:37:36 36.2 28.1 32.1 10.73333 35.06667 −3.03333 9.4 12:37:40 36.228.3 32.1 10.8 35.1 −3 9.5 12:37:44 36.2 28.3 32.1 10.86667 35.1 −3 9.412:37:48 36.2 28 32.1 10.93333 35.06667 −3.03333 9.2 12:37:53 36.2 27.732.1 11.01667 35.06667 −3.03333 9.3 12:37:57 36.2 27.5 32.1 11.0833335.06667 −3.03333 9.3 12:38:01 36.1 27.6 32.1 11.15 35.06667 −3.033339.3 12:38:05 36.1 28 32.1 11.21667 35.06667 −3.03333 9.3 12:38:09 3628.2 32.1 11.28333 35.03333 −3.06667 9.3 12:38:13 36.1 28.1 32.1 11.3535.03333 −3.06667 9.3 12:38:17 36 27.8 32.1 11.41667 35 −3.1 9.312:38:21 36.1 27.5 32.1 11.48333 35.03333 −3.06667 9.3 12:38:25 36.127.5 32.1 11.55 35.03333 −3.06667 9.3 12:38:30 36 27.7 32.1 11.6333334.96667 −3.13333 9.3 12:38:34 36 28.1 32.1 11.7 35 −3.1 9.3 12:38:3836.1 28.1 32.1 11.76667 34.96667 −3.13333 9.3 12:38:42 36.1 27.8 32.111.83333 34.93333 −3.16667 9.4 12:38:46 36.1 27.5 32.1 11.9 34.96667−3.13333 9.5 12:38:50 36.2 27.3 32.1 11.96667 34.96667 −3.13333 9.412:38:55 36 27.5 32.1 12.05 34.96667 −3.13333 9.4 12:38:59 36.1 27.832.1 12.11667 34.93333 −3.16667 9.5 12:39:03 36.1 28.2 32.1 12.1833334.96667 −3.13333 9.5 12:39:07 36.1 28.1 32.1 12.25 34.9 −3.2 9.412:39:11 36.1 27.8 32.1 12.31667 34.93333 −3.16667 9.4 12:39:15 36.127.5 32.1 12.38333 34.93333 −3.16667 9.5 12:39:19 36.1 27.3 32.1 12.4534.93333 −3.16667 9.6 12:39:24 36 27.6 32.1 12.53333 34.9 −3.2 9.412:39:28 36.1 28 32.1 12.6 34.93333 −3.16667 9.3 12:39:32 36 28.2 32.12.66667 34.9 −3.2 9.5 12:39:36 36 28.1 32.1 12.73333 34.93333 −3.166679.5 12:39:40 36 27.8 32.1 12.8 34.86667 −3.23333 9.3 12:39:44 36.1 27.532 12.86667 34.86667 −3.23333 9.3 12:39:49 36.1 27.3 32 12.95 34.86667−3.23333 9.3 12:39:53 36 27.6 32 13.01667 34.83333 −3.26667 9.3 12:39:5736.1 28 32 13.08333 34.83333 −3.26667 9.2 12:40:01 36 28.1 32 13.1534.83333 −3.26667 9.2 12:40:05 36 27.8 32 13.21667 34.83333 −3.26667 9.212:40:09 36.1 27.5 32 13.28333 34.83333 −3.26667 9.2 12:40:13 36.2 27.332.1 13.35 34.83333 −3.26667 9.2 12:40:18 36 27.3 32 13.43333 34.83333−3.26667 9.1 12:40:22 36 27.8 32 13.5 34.83333 −3.26667 9.2 12:40:26 3628.1 32 13.56667 34.83333 −3.26667 9.1 12:40:30 36 27.9 32 13.6333334.83333 −3.26667 9.1 12:40:34 36 27.7 32 13.7 34.83333 −3.26667 9.112:40:38 36 27.3 32 13.76667 34.8 −3.3 9.2 12:40:42 36 27.2 32 13.8333334.83333 −3.26667 9 12:40:47 36 27.5 32 13.91667 34.8 −3.3 8.9 12:40:5135.9 27.9 32 13.98333 34.83333 −3.26667 8.8 12:40:55 35.9 28 32 14.0534.8 −3.3 8.9 12:40:59 35.9 27.6 32 14.11667 34.76667 −3.33333 8.912:41:03 36 27.3 32 14.18333 34.76667 −3.33333 8.8 12:41:07 35.9 27.1 3214.25 34.76667 −3.33333 8.8 12:41:12 36 27.4 32 14.33333 34.8 −3.3 8.812:41:16 36 28 32 14.4 34.76667 −3.33333 8.8 12:41:20 35.9 27.7 3214.46667 34.76667 −3.33333 8.8 12:41:24 36 27.4 32 14.53333 34.76667−3.33333 8.7 12:41:28 36 27.1 32 14.6 34.73333 −3.36667 8.8 12:41:3235.8 27.2 32 14.66667 34.76667 −3.33333 8.8 12:41:36 35.8 27.7 3214.73333 34.7 −3.4 8.9 12:41:41 35.9 27.9 32 14.81667 34.76667 −3.333338.8 12:41:45 35.9 27.7 32 14.88333 34.7 −3.4 8.8 12:41:49 35.8 27.4 3214.95 34.73333 −3.36667 8.8 12:41:53 35.9 27.1 32 15.01667 34.73333−3.36667 8.8 12:41:57 35.8 27.1 32 15.08333 34.76667 −3.33333 9 12:42:0135.8 27.5 32 15.15 34.8 −3.3 8.8 12:42:05 35.7 27.8 32 15.21667 34.8−3.3 8.8 12:42:10 35.9 27.6 32 15.3 34.83333 −3.26667 8.7 12:42:14 35.827.3 32 15.36667 34.8 −3.3 8.8 12:42:18 35.8 27 32 15.43333 34.9 −3.28.8 12:42:22 35.8 27.1 32 15.5 34.9 −3.2 8.8 12:42:26 35.8 27.3 3215.56667 34.9 −3.2 8.6 12:42:30 35.8 27.7 32 15.63333 34.9 −3.2 8.512:42:35 35.9 27.7 32 15.71667 34.96667 −3.13333 8.6 12:42:39 35.9 27.532 15.78333 34.93333 −3.16667 8.5 12:42:43 35.8 27.1 32 15.85 34.96667−3.13333 8.5 12:42:47 35.7 27 32 15.91667 34.93333 −3.16667 8.5 12:42:5135.8 27.2 32 15.98333 34.93333 −3.16667 9.2 12:42:55 35.8 27.6 32 16.0534.93333 −3.16667 9.1 12:42:59 35.8 27.7 32 16.11667 35 −3.1 9.112:43:04 35.9 27.5 32 16.2 35 −3.1 8.9 12:43:08 35.8 27.2 31.9 16.2666734.93333 −3.16667 8.9 12:43:12 35.7 26.8 31.9 16.33333 34.96667 −3.133338.9 12:43:16 35.6 27 32 16.4 34.96667 −3.13333 8.9 12:43:20 35.7 27.4 3216.46667 35.03333 −3.06667 8.7 12:43:24 35.7 27.8 31.9 16.53333 35.1 −38.7 12:43:28 35.8 27.5 31.9 16.6 35.16667 −2.93333 8.7 12:43:33 35.827.3 31.9 16.68333 35.2 −2.9 8.8 12:43:37 35.8 27.1 31.9 16.75 35.23333−2.86667 8.7 12:43:41 35.7 26.8 31.9 16.81667 35.3 −2.8 8.7 12:43:4535.7 27.1 31.9 16.88333 35.33333 −2.76667 8.7 12:43:49 35.8 27.5 31.916.95 35.33333 −2.76667 8.8 12:43:53 35.7 27.6 31.9 17.01667 35.33333−2.76667 8.7 12:43:58 35.6 27.5 31.9 17.1 35.26667 −2.83333 8.9 12:44:0235.8 27.1 32 17.16667 35.36667 −2.73333 8.8 12:44:06 35.7 26.9 3217.23333 35.4 −2.7 8.8 12:44:10 35.6 26.8 31.9 17.3 35.4 −2.7 8.812:44:14 35.5 27.2 31.9 17.36667 35.43333 −2.66667 8.7 12:44:18 35.627.5 31.9 17.43333 35.46667 −2.63333 8.7 12:44:22 35.8 27.6 31.9 17.535.46667 −2.63333 8.7 12:44:27 35.8 27.3 31.9 17.58333 35.53333 −2.566678.6 12:44:31 35.8 27.1 31.9 17.65 35.5 −2.6 8.6 12:44:35 35.8 26.8 31.917.71667 35.53333 −2.56667 8.6 12:44:39 35.7 26.8 31.8 17.78333 35.5−2.6 8.4 12:44:43 35.6 27.2 31.8 17.85 35.53333 −2.56667 8.5 12:44:4735.7 27.5 31.9 17.91667 35.53333 −2.56667 8.5 12:44:52 35.8 27.5 31.8 1835.5 −2.6 8.6 12:44:56 35.7 27.1 31.8 18.06667 35.53333 −2.56667 8.812:45:00 35.5 26.8 31.9 18.13333 35.53333 −2.56667 8.8 12:45:04 35.6 2731.8 18.2 35.6 −2.5 8.7 12:45:08 35.7 27.4 31.8 18.26667 35.6 −2.5 8.512:45:12 35.7 27.5 31.8 18.33333 35.6 −2.5 8.5 12:45:17 35.7 27.3 31.818.41667 35.6 −2.5 8.5 12:45:21 35.7 27 31.8 18.48333 35.63333 −2.466678.5 12:45:25 35.6 26.7 31.8 18.55 35.66667 −2.43333 8.3 12:45:29 35.526.8 31.8 18.61667 35.66667 −2.43333 8.4 12:45:33 35.6 27.4 31.818.68333 35.66667 −2.43333 8.6 12:45:37 35.8 27.5 31.8 18.75 35.7 −2.48.5 12:45:41 35.7 27.2 31.8 18.81667 35.63333 −2.46667 8.5 12:45:46 35.627 31.8 18.9 35.6 −2.5 8.6 12:45:50 35.6 26.7 31.8 18.96667 35.63333−2.46667 8.6 12:45:54 35.7 26.8 31.7 19.03333 35.6 −2.5 8.5 12:45:5835.7 27.3 31.8 19.1 35.63333 −2.46667 8.5 12:46:02 35.7 27.6 31.819.16667 35.66667 −2.43333 8.5 12:46:06 35.6 27.3 31.8 19.23333 35.7−2.4 8.6 12:46:10 35.6 27 31.8 19.3 35.7 −2.4 8.5 12:46:15 35.6 26.831.8 19.38333 35.66667 −2.43333 8.3 12:46:19 35.7 26.9 31.8 19.4535.73333 −2.36667 8.4 12:46:23 35.6 27.2 31.8 19.51667 35.73333 −2.366678.4 12:46:27 35.7 27.6 31.8 19.58333 35.76667 −2.33333 8.5 12:46:31 35.727.4 31.8 19.65 35.76667 −2.33333 8.5 12:46:35 35.6 27.2 31.8 19.7166735.8 −2.3 8.4 12:46:40 35.5 26.9 31.8 19.8 35.8 −2.3 8.3 12:46:44 35.626.7 31.8 19.86667 35.8 −2.3 8.2 12:46:48 35.6 27.1 31.8 19.93333 35.8−2.3 8.2 12:46:52 35.6 27.5 31.8 20 35.83333 −2.26667 8.1 12:46:56 35.627.5 31.8 20.06667 35.8 −2.3 8.1 12:47:00 35.7 27.2 31.8 20.1333335.83333 −2.26667 8.2 12:47:04 35.7 27 31.8 20.2 35.8 −2.3 8.3 12:47:0835.7 26.7 31.8 20.26667 35.8 −2.3 8.2 12:47:13 35.6 27 31.8 20.35 35.8−2.3 8.1 12:47:17 35.7 27.2 31.8 20.41667 35.83333 −2.26667 8.1 12:47:2135.6 27.5 31.8 20.48333 35.83333 −2.26667 8.2 12:47:25 35.5 27.3 31.820.55 35.8 −2.3 8.4 12:47:29 35.6 27.1 31.8 20.61667 35.86667 −2.233338.3 12:47:33 35.7 26.8 31.8 20.68333 35.8 −2.3 8.3 12:47:37 35.7 26.731.8 20.75 35.86667 −2.23333 8.2 12:47:42 35.7 27 31.8 20.83333 35.83333−2.26667 8.2 12:47:46 35.7 27.3 31.8 20.9 35.86667 −2.23333 8.2 12:47:5035.7 27.5 31.8 20.96667 35.8 −2.3 8.2 12:47:54 35.7 27.5 31.8 21.0333335.83333 −2.26667 8.2 12:47:58 35.7 27.2 31.8 21.1 35.9 −2.2 8.212:48:02 35.6 26.9 31.8 21.16667 35.9 −2.2 8.2 12:48:07 35.6 26.7 31.821.25 35.9 −2.2 8.2 12:48:11 35.5 26.8 31.8 21.31667 35.9 −2.2 8.112:48:15 35.5 27.1 31.8 21.38333 35.9 −2.2 8.2 12:48:19 35.6 27.5 31.821.45 35.83333 −2.26667 8.1 12:48:23 35.6 27.3 31.8 21.51667 35.83333−2.26667 8.1 12:48:27 35.6 27.1 31.8 21.58333 35.86667 −2.23333 8.212:48:32 35.6 26.8 31.8 21.66667 35.86667 −2.23333 11.1 12:48:36 35.526.7 31.8 21.73333 35.86667 −2.23333 12.8 12:48:40 35.5 27.3 31.8 21.835.83333 −2.26667 12.7 12:48:44 35.5 27.6 31.8 21.86667 35.86667−2.23333 13.2 12:48:48 35.5 27.4 31.7 21.93333 35.86667 −2.23333 13.812:48:52 35.6 27 31.7 22 35.86667 −2.23333 14 12:48:56 35.5 26.7 31.722.06667 35.83333 −2.26667 14.5 12:49:00 35.5 26.7 31.7 22.1333335.86667 −2.23333 10 12:49:05 35.3 27.1 31.7 22.21667 35.83333 −2.266679.6 12:49:09 35.4 27.5 31.7 22.28333 35.86667 −2.23333 8.9 12:49:13 35.627.3 31.7 22.35 35.83333 −2.26667 8.6 12:49:17 35.5 27.2 31.7 22.4166735.83333 −2.26667 8.5 12:49:21 35.5 26.9 31.8 22.48333 35.8 −2.3 8.612:49:25 35.5 26.8 31.8 22.55 35.8 −2.3 8.5 12:49:30 35.5 27.2 31.722.63333 35.76667 −2.33333 8.4 12:49:34 35.5 27.6 31.7 22.7 35.73333−2.36667 8.4 12:49:38 35.5 27.5 31.7 22.76667 35.73333 −2.36667 8.512:49:42 35.6 27.4 31.7 22.83333 35.73333 −2.36667 8.4 12:49:46 35.6 2731.7 22.9 35.73333 −2.36667 8.3 12:49:50 35.6 26.8 31.7 22.9666735.73333 −2.36667 8.3 12:49:55 35.6 27 31.7 23.05 35.73333 −2.36667 8.312:49:59 35.5 27.4 31.7 23.11667 35.73333 −2.36667 8.4 12:50:03 35.527.6 31.7 23.18333 35.7 −2.4 8.4 12:50:07 35.5 27.5 31.7 23.25 35.7 −2.48.3 12:50:11 35.6 27.2 31.7 23.31667 35.7 −2.4 8.3 12:50:15 35.5 26.831.7 23.38333 35.66667 −2.43333 8.3 12:50:20 35.5 26.8 31.7 23.4666735.63333 −2.46667 8.3 12:50:24 35.5 27.2 31.7 23.53333 35.63333 −2.466678.3 12:50:28 35.5 27.6 31.7 23.6 35.63333 −2.46667 8.2 12:50:32 35.527.5 31.7 23.66667 35.63333 −2.46667 8.2 12:50:36 35.5 27.3 31.723.73333 35.63333 −2.46667 8.3 12:50:40 35.5 27 31.7 23.8 35.63333−2.46667 8.3 12:50:44 35.5 26.8 31.7 23.86667 35.6 −2.5 8.2 12:50:4935.5 27.1 31.7 23.95 35.56667 −2.53333 8.5 12:50:53 35.3 27.5 31.624.01667 35.53333 −2.56667 8.3 12:50:57 35.3 27.5 31.6 24.08333 35.53333−2.56667 8.3 12:51:01 35.5 27.3 31.6 24.15 35.5 −2.6 8.2 12:51:05 35.527 31.7 24.21667 35.5 −2.6 8.2 12:51:10 35.4 26.8 31.7 24.3 35.46667−2.63333 8.2 12:51:14 35.3 26.9 31.7 24.36667 35.46667 −2.63333 8.212:51:18 35.3 27.3 31.7 24.43333 35.5 −2.6 8.1 12:51:22 35.4 27.6 31.724.5 35.46667 −2.63333 8.2 12:51:26 35.3 27.4 31.6 24.56667 35.43333−2.66667 8.2 12:51:30 35.3 27.1 31.7 24.63333 35.43333 −2.66667 8.212:51:34 35.3 26.9 31.7 24.7 35.43333 −2.66667 8.1 12:51:39 35.3 26.831.7 24.78333 35.4 −2.7 8.1 12:51:43 35.3 27.1 31.6 24.85 35.4 −2.7 812:51:47 35.3 27.5 31.7 24.91667 35.4 −2.7 8 12:51:51 35.3 27.5 31.624.98333 35.4 −2.7 8 12:51:55 35.3 27.2 31.6 25.05 35.4 −2.7 8 12:51:5935.3 27.1 31.7 25.11667 35.4 −2.7 8.1 12:52:04 35.3 26.8 31.6 25.2 35.4−2.7 8 12:52:08 35.3 26.9 31.6 25.26667 35.4 −2.7 8 12:52:12 35.3 27.331.6 25.33333 35.4 −2.7 8.1 12:52:16 35.3 27.6 31.7 25.4 35.36667−2.73333 8.1 12:52:20 35.3 27.4 31.6 25.46667 35.36667 −2.73333 8.112:52:24 35.3 27.1 31.6 25.53333 35.36667 −2.73333 8 12:52:28 35.2 26.831.6 25.6 35.36667 −2.73333 8 12:52:32 35.3 27.1 31.6 25.66667 35.3 −2.88.1 12:52:37 35.3 27.5 31.6 25.75 35.3 −2.8 8.1 12:52:41 35.2 27.4 31.625.81667 35.3 −2.8 8.1 12:52:45 35.3 27.2 31.6 25.88333 35.26667−2.83333 8 12:52:49 35.3 26.9 31.6 25.95 35.3 −2.8 8 12:52:53 35.2 26.831.6 26.01667 35.3 −2.8 8.1 12:52:58 35.2 27 31.6 26.1 35.26667 −2.833338 12:53:02 35.2 27.4 31.6 26.16667 35.26667 −2.83333 7.9 12:53:06 35.327.5 31.6 26.23333 35.26667 −2.83333 7.9 12:53:10 35.3 27.4 31.6 26.335.3 −2.8 8.1 12:53:14 35.3 27.1 31.6 26.36667 35.26667 −2.83333 812:53:18 35.2 26.9 31.6 26.43333 35.26667 −2.83333 8 12:53:22 35.2 26.831.6 26.5 35.23333 −2.86667 8 12:53:27 35.2 27.1 31.6 26.58333 35.26667−2.83333 8 12:53:31 35.2 27.5 31.6 26.65 35.26667 −2.83333 7.9 12:53:3535.2 27.5 31.6 26.71667 35.23333 −2.86667 8 12:53:39 35.2 27.3 31.626.78333 35.26667 −2.83333 8 12:53:43 35.2 27 31.6 26.85 35.23333−2.86667 8 12:53:47 35.1 26.8 31.6 26.91667 35.23333 −2.86667 8 12:53:5135.3 26.9 31.6 26.98333 35.23333 −2.86667 8 12:53:55 35.4 27.2 31.627.05 35.23333 −2.86667 7.9 12:54:00 35.5 27.5 31.6 27.13333 35.23333−2.86667 8 12:54:04 35.4 27.4 31.6 27.2 35.23333 −2.86667 8 12:54:0835.4 27.1 31.6 27.26667 35.23333 −2.86667 7.8 12:54:12 35.4 26.8 31.627.33333 35.23333 −2.86667 7.8 12:54:16 35.1 26.8 31.6 27.4 35.23333−2.86667 7.8 12:54:20 35 27.1 31.6 27.46667 35.23333 −2.86667 8 12:54:2435 27.5 31.6 27.53333 35.23333 −2.86667 8 12:54:29 34.8 27.5 31.627.61667 35.23333 −2.86667 7.8 12:54:33 34.8 27.3 31.6 27.68333 35.23333−2.86667 7.8 12:54:37 34.9 27 31.6 27.75 35.26667 −2.83333 7.4 12:54:4135 26.8 31.6 27.81667 35.23333 −2.86667 8.7

FIG. 39 illustrates nasal catheter 910 for non-invasive cerebral andsystemic cooling of the nasal cavity. The nasal catheter has a roundedsealed tip 912 on the distal end, which provides a smooth surface toavoid damaging sensitive tissues. Tip 912 may be sealed by selectivemelting of the distal end of the catheter. In use, catheter 910 isintended to be placed in the nares of the nose, so that a spray outlet(not shown) may be directed at the desired structures of the nasalcavity, specifically the nasal conchae. The spray nozzle on the distalend of nasal catheter 10 is designed so as to cause the spray to spreadin a pattern which will allow the gas/liquid mixture to contact as muchof the desired tissues as possible. By doing this, any mechanical traumadue to a concentrated high velocity jet should be minimized.

FIGS. 43A-C depict several possible designs for the spray nozzle forcreating varying spread spray patterns. FIG. 43A shows nasal catheter910 wherein the spray nozzle has been formed by drilling multiple holes940 along the outer wall of nasal catheter 910. In use, this patternproduces will produce a broad, flat spray perpendicular to the axis ofthe catheter. This pattern may be further customized by drillingcorresponding holes in the opposite side of the catheter wall (notshow), or by changing the size, location and number of holes drilled inthe catheter outer wall. In addition, it may also be possible to includea hole in the catheter tip 12 (hole not shown), to produce someadditional flow in the axial direction.

FIG. 43B shows nasal catheter 910, wherein the spray nozzle has beenformed by cutting a rectangular slit 942 in tip 912 of catheter 910. Inuse, this pattern produces a fan shaped spray centered along the axialdirection of the catheter. Here, the width and length of slit 942 willdictate the character of the spray. The pattern may, therefore becustomized by varying the width and length of slit 942. In addition, thesymmetry of the spray may be altered by cutting slit 942 to extendfarther down one side catheter 910 than the other. Alternatively, thespray pattern may be altered by adding one or more additional slits ofvarying widths and lengths (not shown).

FIG. 43C shows a nasal catheter 910, wherein the spray nozzle has beenformed by making an angled straight cut 944 or a curved cut (not shown)in the side of catheter 910, including a portion of catheter tip 912. Inuse, this skived cut produces a wide ‘fan’ shaped spray which covers abroad angle from the perpendicular to the axial directions of catheter910. In addition, any of the patterns depicted in FIGS. 43A-C could alsobe combined to further disperse the spray. For example, holes could becut along the length of a skived tip catheter to cover a wider area, ora slit could be cut in the tip of a the drilled hole catheter to enhanceflow in the axial direction.

FIG. 40 shows a dual-lumen mixing catheter 914 connected to two nasalcatheters 910 for separately delivering a liquid and a gas to theproximal end of each nasal catheter 910. In use, nasal catheters 910will be placed a distance apart appropriate for the nares of the desiredpatient, and made a length appropriate for administration at thetargeted tissues. The dual-lumen mixing catheter 914 comprises an upperlumen 918 and a lower lumen 920 used to separately deliver the liquidand the gas. This mixing catheter may be constructed as a single endeddevice, or made into a loop (not shown) similar to a standard nasalcannula for oxygen therapy. The ‘loop’ configuration aids in placementon the patient, as it may be routed over and behind the ears to hold itin place. The loop configuration also helps ensure equal flow when twonasal catheters are used.

Nasal catheter 910 is connected to mixing catheter 914 by a connectingtube 916. Connecting tube 916 is a hollow, open ended tube for attachingnasal catheter 910 to mixing catheter 914 and for placing nasal catheter910 in fluid communication with at least the lower lumen 920 of mixingcatheter 914. It can be made from metal ‘hypodermic’ tubing, or asuitable plastic. As shown in FIG. 41, the connecting tube 916 has anouter diameter sized to fit tightly in the lumen of nasal catheter 910and thus form a seal between nasal catheter 910 and mixing catheter 914.Once assembled, an over layer of glue or other compound such as siliconemay be used to ensure a durable connection and smooth texture forpatient comfort. In use, open ended, hollow tube 924 of connecting tube916 places the lumen of nasal catheter 910 in fluid communication withthe lower lumen 920 of mixing catheter 910. In this configuration, thegas is supplied through the lower lumen 920 of the dual lumen tubing914. The gas flows through the lower lumen 920 and up through the lumen924 of connecting tube 916 into the nasal catheter(s) 910. At the sametime, the liquid is supplied through the upper lumen 918 of mixingcatheter 914. The liquid passes into the lumen 924 of connecting tube916 via a small hole 922 drilled in the wall of connecting tube 916. Theinner diameter of the tube and the size of fluid hole 922 are importantparameters in the optimization of the spray pattern.

At this point, the gas is moving at a high velocity, and the liquidexperiences high shear forces, breaking the stream into small dropletsthat then flow through the lumen of nasal catheter 910 and are deliveredas a spray to the patient's nasal cavity through the spray nozzle 915.

FIG. 42 illustrates an alternate embodiment of a mixing catheter. Thedual lumen tubing 914 is used as above, and catheter tip 912, includinga spray nozzle 915 is also as previously described. In this embodiment,however, the mixing of the air and liquid occurs very near tip 912. Theliquid is delivered through lower lumen 930 and the gas is deliveredthrough upper lumen 928 of mixing catheter 914. The nasal catheter issecured directly to an aperture in upper lumen 928 so that a smalldiameter liquid delivery tube 926 extending perpendicularly from lowerlumen 930 of mixing catheter 914 is positioned inside the lumen of thenasal catheter 910. Liquid tube 926 is a hollow, open ended tubeextending through the lumen of nasal catheter 910 to the distal regionof nasal catheter 910. Liquid tube 926 has an outer diameter smallerthan the inner diameter of nasal catheter 910 and smaller than theaperture connecting nasal catheter 910 to mixing catheter 914. In use,the liquid flows through lumen 927 of liquid tube 926 while the gasflows through upper lumen 928 and enters nasal catheter 910 via theannular space 929 between liquid tube 926 and the inside diameter ofcatheter 910. Turbulence and other flow effects, such as Bernoullipressure, at the end of liquid tube 926 cause the fluid to be broken upinto small droplets. This design requires less pressure to drive theliquid, and may aid in matching the liquid and gas flows.

FIG. 44 illustrates an alternative embodiment of a gas and liquiddelivery system that may be attached the proximal end of the nasalcatheter whereby the liquid and the gas are delivered to the catheterthrough their own tubes 950 and 952 and mixed at the point ofadministration to the patient, rather than prior to use. This ensuresthat even an unstable spray can be delivered to the desired region.Furthermore, because the liquid begins to evaporate immediately uponcontact with the gas, mixing at the point of use in the patient willensure efficient use of all available cooling. As seen in FIG. 44, themixing device may comprise a mixing block 954 including at least twoinput flow channels 950 and 952 and a single output flow channel 956.Mixing block 954 may be machined from metal, plastic, or molded fromplastic. The two input flow channels 950 and 952 may be connected to twoseparate tubes containing a liquid and a compressed gas. Input channels950 and 952 may then be joined in mixing block 954 so that the liquidand gas carried by the input tubes will be combined, after which thecombined liquid/gas mixture may then flow through output channel 956.The nasal catheter may be attached to output channel 956 for delivery ofthe combined liquid/gas mixture to the patient's nasal cavity.

FIG. 46 illustrates an alternative nasal catheter for cooling the nasalcavity with cold saline. Here, nasal catheter 990 includes an elongatetubular member, operably sized to extend into the patient's nasopharynxwith expandable member 992 mounted on the distal end of catheter 990. Inuse, nasal catheter 990 is inserted into one of the patient's nostrilsand positioned in the nasopharynx. Once positioned in the nasopharynx,expandable member 992 is expanded to conform to the nasopharynx and forma seal isolating the nasal cavity from the rest of the patient'sairways. Once isolated, cold saline is injected into one of thepatient's nostrils and circulated though the nasal cavity to allow forrapid cooling of the patient's head. Expandable member 992 prevents thesaline from entering the patients other airways. The saline may then beallowed to run out the patient's other nostril or may be suctioned fromthe patient's nasal cavity from a suction port (not shown) proximal toexpandable member 992. In addition, a second nasal catheter (not shown),also comprising an elongate tubular member with an expandable membermounted on the distal end, may be inserted in the patient's secondnostril. Here, the balloons may be positioned on either side of thenasal cavity before the septum and expanded to isolate the nasal cavityfrom the rest of the patient's airways.

FIGS. 47-48 show an alternative nasal catheter for cooling the nasalcavity with a cold liquid. Here, nasal catheter 990 includes an elongatetubular member, operably sized to extend into the patients nasopharynxand at least one expandable member 992 mounted near the distal end ofthe elongate tubular member and two expandable members 991 a-b mountednear the proximal end of catheter 990. In use, nasal catheter 990 isinserted into one of the patient's nostrils and positioned in thenasopharynx. Once positioned in the nasopharynx, expandable member 992is expanded to conform to the nasopharynx and form a seal isolating thenasal cavity from the rest of the patient's airways and the expandablemembers 991 a-b at the proximal end are positioned in the patientsnostrils to seal the patient's nasal cavity. Alternatively, as depictedin FIG. 48, the distal end may have two expandable members 992 a-b thatmay be positioned at the posterior aspect of the nasal cavity to isolatethe nasal cavity from the pharynx. Catheter 990 also has openings 994and 995 at the distal and proximal ends, respectively, to provide abreathing passage while the nasal cavity is sealed. Once the nasalcavity is isolated, a cold fluid may be delivered to the nasal cavityvia delivery lumen 997, which is in fluid communication with port 996.Alternatively, a tube comprising a spray nozzle (not shown) may beinserted in the delivery lumen 997 to deliver a liquid spray to thenasal cavity.

Expandable members 992 a-b and 991 a-b at the distal and proximal endsof catheter 990 prevent non-vaporized fluid from leaking into the throator running out the patient's nostrils. The non-vaporized liquid may thenbe suctioned from the nasal cavity via suction lumen 999, which is influid communication with port 998. This liquid may be discarded oralternatively it may be recycled for successive use. Because there is adedicated lumen for delivery and suction, however, delivery of thecooled liquid to the nasal cavity does not need to be interrupted.

Convective Cooling in the Nasal Cavity

In another aspect of this invention, a catheter with a flexible balloonhaving a chamber filled with a cooling liquid can be used to cool thebrain via the nasal cavity. As seen in FIG. 22A, assembly 200 includesflexible balloon 204 that is mounted circumferentially around catheter202. Catheter 202 has ports 211, 212 at the proximal and distal ends andlumen 210 extending therebetween that enables the patient to breathewhile the catheter is in use. Ports 211, 212 and lumen 210 are in fluidcommunication with the patient's nasopharynx, pharynx, larynx, and/oresophagus. Catheter 202 is approximately 8 cm in length, alternativelyapproximately 10 cm in length, alternatively approximately 12 cm inlength, alternatively approximately 14 cm in length, alternativelyapproximately 16 cm in length, alternatively approximately 18 cm inlength, alternatively approximately 20 cm in length. Lumens 206, 208 arein fluid communication with the chamber of the flexible balloon 204through ports 207, 209 located at the distal ends. At their proximalends, lumens 204, 206 are connected to a refrigerated pump (not shown)that is capable of recycling a cooling fluid through the chamber of theflexible balloon 204.

In use, as seen in FIG. 22B, assembly 200 is inserted into the nasalcavity through the patient's nostril such that flexible balloon 204 iswithin the nasal cavity and the distal end of catheter 202 extendsthrough the narices to the nasopharyngeal region of the nasal cavity. Acooling liquid or fluid can then be used to inflate or infuse thechamber of flexible balloon 204 to a sufficient pressure such thatflexible balloon 204 expands and is in contact with a substantialportion of the nasal cavity. The cooling fluid may then be recirculatedthrough the chamber of flexible balloon 204 via lumens 206, 208 and arefrigerated bath/pump (not shown). Optionally, the cooling fluid can bewithdrawn or suctioned back out of flexible balloon 204 at a ratesufficient to induce or maintain a desired balloon pressure or braintemperature. Additionally, a second assembly can also be inserted intothe other nostril such that maximum cooling can be obtained. The coolingof the brain would occur by convection or heat exchange from the coldliquid in the chamber of the balloon to the warm nasal cavity. Lumen 210of catheter 202 allows the patient to breathe through his nose after theflexible balloon 204 is inflated. Alternatively, when the patient isgetting oxygen through alternative means, other medical devices can bepassed through lumen 210. These medical devices include, but are notlimited to, oxygen tube, nasogastric tube, fiber optics, laryngoscope,pH probes, and esophageal manometry.

In an alternative embodiment, a flexible balloon having a chamber filledwith a cooling liquid can be used to cool the brain via the nasalcavity. As seen in FIG. 23A, assembly 250 includes flexible balloon 254that has a chamber that is in fluid communication with lumens 256, 258of elongate tubular members 264, 268 through ports 257, 259 located attheir distal ends. At their proximal ends, elongate tubular members 264,268 may be connected to cooler 260 and pump 262 that infuse and/orrecirculate the cooling liquid through lumens 256, 258 and the chamberof flexible balloon 254. Alternatively, elongate tubular members 264,268 may be connected to a refrigerated pump (not shown) that is capableof pumping and/or recirculating the cooling fluid.

In use, as seen in FIG. 23B, assembly 250 is inserted into the nasalcavity through a nostril such that flexible balloon 254 is within thenasal cavity 270. A cooling fluid can then be used to inflate flexibleballoon 254 to a sufficient pressure such that flexible balloon 254expands and is in contact with a substantial portion of the nasalcavity. The cooling fluid is then recirculated through flexible balloon254 via lumens 256, 258, cooler 260, and pump 262. Optionally, thecooling fluid can be suctioned back out of flexible balloon 254 at arate sufficient to induce or maintain a desired balloon pressure orbrain temperature. Additionally, a second assembly can also be insertedinto the other nostril such that maximum cooling can be obtained. Thecooling of the brain would occur by convection or heat exchange from thecold liquid in the balloon to the warm nasal cavity.

In an alternative embodiment, a flexible balloon having a chamber filledwith a cooling liquid can be used to cool the brain via the nasalcavity. As seen in FIG. 29, assembly 700 includes flexible balloon 702that has a chamber 703 that is in fluid communication with lumen 706 ofelongate tubular member 708 through port 710 located at its distal end.At a point outside of chamber 703, elongate tubular member 708 branchesinto two elongate tubular members 715 and 720 having lumens 716 and 721,respectively. Elongate tubular members 720 and 715 are in communicationwith each other through pump 722, e.g., a piston pump, and cooler 724,located at or near the proximal ends of elongate tubular members 715 and720. Cooler 724 and pump 722 infuse and/or recirculate the coolingliquid through lumens 716 and 721 and the chamber of flexible balloon254. This single lumen design may allow for faster inflation anddeflation. Alternatively, elongate tubular members 715 and 720 may beconnected to a refrigerated pump (not shown) that is capable of pumpingand/or recirculating the cooling fluid.

In use, assembly 700 is inserted into the nasal cavity through a nostrilsuch that flexible balloon 702 is within the nasal cavity. A coolingfluid can then be used to inflate flexible balloon 702 to a sufficientpressure such that flexible balloon 702 expands and is in contact with asubstantial portion of the nasal cavity. The cooling fluid is thenrecirculated through flexible balloon 702 via lumens 706, 716, and 721,cooler 722, and pump 724. For instance, cooling liquid may be withdrawnfrom chamber 703 by having pump 722 withdraw the cooling liquid throughlumens 706 and 721 of elongate tubular members 708 and 720,respectively. Cooling liquid can then be pumped into cooler for furthercooling and then pumped back into chamber 703 through lumens 716 and 706of elongate tubular members 715 and 708. In order to optimize coolingand minimize tissue damage, it may be desirable to continuously inflateand deflate flexible balloon 702. Additionally, a second assembly canalso be inserted into the other nostril such that maximum cooling can beobtained. The cooling of the brain would occur by convection or heatexchange from the cold liquid in the balloon to the warm nasal cavity.

In an alternative embodiment, a flexible balloon having a chamber filledwith a cooling liquid and a cold finger inside of a second balloon canbe used to cool the brain via the nasal cavity. As seen in FIG. 27,assembly 600 includes flexible balloon 602 that has chamber 603 that isin fluid communication with port 604. A cooling liquid, such as water orsaline, can be infused into chamber 603 through port 604. A secondballoon 605 containing a cold probe 607 is contained within chamber 603to cool the liquid inside flexible balloon 602. A cooling agent, such asFreon or other PFC, that is approximately 0° C., alternativelyapproximately −1° C., alternatively approximately −2° C., alternativelyapproximately −3° C., alternatively between about −5° C. and 5° C.,alternatively between about −5° C. and 0° C., will be flowed throughcold probe 607. The flow rate of the cooling agent will depend on thetype used. The flow rate will be chosen to produce between about 150 andabout 300 watts. Additionally, cold probe 607 may be connected to cooler610. Second balloon 605 may be in fluid communication with a port andallowed to vent to the atmosphere (not shown). Alternatively, secondballoon 605 may be in fluid communication with a compressor 612 throughelongate tubular member 614 to circulate the cooling liquid.

Cold probe 607 may also have fins surrounding the cold probe (not shown)to increase the surface area of the probe. Alternatively, a heat pipecould be used in place of the cold probe. The heat pipe could be filledwith a gas such as freon or ammonia, or alternatively, the heat pipecould be connected to a circulating cooling liquid reservoir or othercooling source (such as a block of ice).

In use, assembly 600 is inserted into the nasal cavity through thepatient's nostril such that flexible balloon 602 is within the nasalcavity. A cooling fluid can then be used in inflate flexible balloon 602to a sufficient pressure such that flexible balloon 602 expands and isin contact with a substantial portion of the nasal cavity. The coolingagent will then be circulated into second balloon 605 via port 608 atthe distal end of cold probe 607 and elongate tubular member 614.Alternatively, the cooling agent may not be recirculated, but rather bevented out of a port in second balloon 605 (not shown). Additionally,the fluid in the balloon can be agitated to prevent freezing. This maybe accomplished by moving cold probe 607 or pulsing the infusion of thecooling agent into second balloon 605. Additionally, a second assemblycan also be inserted into the other nostril such that maximum coolingcan be obtained. The cooling of the brain would occur by convection orheat exchange from the cold liquid in the balloon to the warm nasalcavity.

In an alternative embodiment, a flexible balloon having a chamber filledwith a cooling liquid and a cold finger can be used to cool the brainvia the nasal cavity. As seen in FIG. 28A, assembly 650 includesflexible balloon 652 that has chamber 653 that is in fluid communicationwith port 654 containing a filter 656. A cooling liquid, such as wateror saline, can be infused into chamber 653 through lumen 658 of elongatetubular member 659. A cooling agent, such as Freon or other PFC, that isapproximately 0° C., alternatively approximately −1° C., alternativelyapproximately −2° C., alternatively approximately −3° C., alternativelybetween about −5° C. and 5° C., alternatively between about −5° C. and0° C., will be flowed through cold probe 657. Additionally, cold probe657 may be connected to cooler (not shown). The cooling agent will flowout of port 658 of cold probe 657 and produce gas bubbles 660 in thecooling liquid in chamber 653, thereby cooling the liquid further andagitating the liquid to aid in mixing the liquid throughout chamber 653.The gas bubbles can exit chamber 653 through port 654 with air ventingfilter 656, which allows for the release of gas and not liquid.Additionally, an additional elongate tubular member (not shown) can beinserted into flexible balloon 652 such that a lumen of the elongatetubular member is in fluid communication with chamber 653 of balloon652. An additional gas, such as oxygen or nitrogen, can be deliveredinto the cooling liquid to aid in the mixing and agitation of thecooling liquid within the chamber.

In use, with the patient lying on his back, assembly 650 is insertedinto the nasal cavity through the patient's nostril such that flexibleballoon 652 is within nasal cavity 670. A cooling fluid can then be usedin inflate flexible balloon 652 to a sufficient pressure such thatflexible balloon 652 expands and is in contact with a substantialportion of nasal cavity 670. The cooling agent will flow out of port 658of cold probe 657 and produce gas bubbles 660 in the cooling liquid inchamber 653, thereby cooling the liquid further and agitating the liquidto aid in mixing the liquid throughout chamber 653. The gas bubbles canexit chamber 653 through port 654 with air venting filter 656, whichallows for the release of gas and not liquid. Additionally, the fluid inthe balloon can be agitated to prevent freezing. This may beaccomplished by moving cold probe 657 or pulsing the infusion of thecooling agent into chamber 653. Additionally, a second assembly can alsobe inserted into the other nostril such that maximum cooling can beobtained. The cooling of the brain would occur by convection or heatexchange from the cold liquid in the balloon to the warm nasal cavity.

Flexible balloons for use in the nasal cavity are sized such that uponinflation, they are capable of making good contact with the surfaces ofthe nasal cavity, including the portion of the cavity that liesposterior to the cavernous sinus. In one embodiment, the length of theflexible balloon will depend upon the size of the nasal cavity and maybe less than 15 cm long, alternatively less than 14 cm long,alternatively less than 13 cm long, alternatively less than 12 cm long,alternatively less than 11 cm long, alternatively less than 10 cm long,alternatively less than 9 cm long, alternatively less than 8 cm long.The flexible balloons may also have the shape of the nasal cavity.Alternatively, as seen in FIG. 30, flexible balloon 750 may have a shapecontaining multiple fingers such that, upon inflation, one or morefingers will have the opportunity to extend into and fill the meatus(superior, middle, and/or inferior) to maximize contact with the tissuesin the nasal cavity. Alternatively, the flexible balloon may havemultiple lobes to accomplish the same purpose of extending into andfilling the meatus. The flexible balloons are also preferably oversizedand made of a soft, conformable, elastomeric material to provide maximumsurface contact with the nasal cavity. The assemblies may also include acheck valve (not shown) that will release fluid, thereby reducing thepressure of the flexible balloons when they reach a certain pressure.Optionally, the flexible balloons may be made of a porous material thatallows for the controlled release of drugs to the nasal cavity. Examplesof materials for the elastomeric, flexible balloons include, but are notlimited to, urethanes, vinyl (PVC), silicone. Examples of non-elasticmaterials include, but are not limited to, mylar, polyethylene,polypropylene, polystyrene, and polyvinylacetate.

In use, the pressure in these flexible balloons for use in the nasalcavity can oscillate between lower and higher pressures. In other words,the fluid can be infused to fill the chamber defined by the ballooneither slowly or quickly. When expanded at higher pressures, presumablymore heat transfer will occur due to increased contact with the nasalcavity. Extended periods at higher pressures, however, may not bedesirable due to possible problems with stopping blood flow in thesurrounding tissue. Additionally, the act of pulsing the liquid wouldresult in increased circulation of the liquid. Rapid pulsing, for thepurposes of mixing the liquid within the balloon chamber, could rangefrom about 0.5 to about 200 Hz, alternatively from about 1 to about 150Hz, alternatively from about 1 to about 100 Hz, alternatively from about10 to about 100 Hz, alternatively from about 25 to about 100 Hz. Slowerpulsing could be used to effect physiologic responses, such as deflatingthe balloon to allow blood flow to resume circulation in the cooledarea. Slower pulsing could range from about one inflation per second toabout one inflation per 10 minutes, alternatively from about oneinflation per second to about one inflation per 5 minutes, alternativelyfrom about one inflation per second to about one inflation per 3minutes. Alternatively, the balloon could be inflated approximately onceevery 30 seconds, alternatively once every 1 minute, alternatively onceevery 2 minutes, alternatively once every 3 minutes, alternatively onceevery 4 minutes, alternatively once every 5 minutes, alternatively onceevery 6 minutes, alternatively once every 7 minutes, alternatively onceevery 8 minutes, alternatively once every 9 minutes, alternatively onceevery 10 minutes. During these slower cycling periods, the balloon couldremain inflated for approximately 1% of the cycling period,alternatively approximately 5% of the cycling period, alternativelyapproximately 10% of the cycling period, alternatively approximately 20%of the cycling period, alternatively approximately 30% of the cyclingperiod, alternatively approximately 40% of the cycling period,alternatively approximately 50% of the cycling period.

Cooling Calculations

The following calculations estimate the maximum cooling that can beobtained when a chilled liquid is circulated through the nasal cavity,where the chilled fluid is either directly in contact with the nasaltissues or contained in a flexible membrane ‘balloon’ within the nose.

A cooling liquid is circulated into and out of the nasal cavity. Thefollowing calculations are done assuming that the chilled fluid will bean aqueous fluid. The following are properties of water:

-   -   Density: 1 gram/ml    -   Heat capacity: 1 cal/gram-° C.

The liquid will enter the nasal cavity at a temperature well below bodytemperature, and exit at a warmer temperature. The warming of the waterwill be equal to the cooling of the body, so the calculations for heatadded to the water is the same as that for heat removed from the body.

Q′=c*m*(T2−T1) or Q′=cmΔT  Equation 1

-   -   Q′=the rate of heat transfer    -   m=the mass flow rate of the liquid administered    -   c=the heat capacity of the liquid    -   T1=the temperature of the liquid at administration    -   T2=the temperature to which the liquid is warmed

If the flow rate is 500 ml/min, inlet temperature is 2° C., outlettemperature is 4° C.

Heat Transfer=500 ml/min*1 g/ml*1 cal/gm ° C.*(4° C.−2° C.)=1000 cal/min

Conversion factors: 1 calorie/minute=0.069 78 watt 1000 cal/min*0.06978Watt/cal/min=70 Watts

The cooling of the whole body can be calculated using the same equationas above. The heat capacity of the human body is generally accepted tobe 0.85 cal/gm ° C. For this calculation, other sources of heat enteringor leaving the body, and heat generated in the body are neglected, as itis likely those aspects balance out in a stable patient. Coolingtherefore reduces to the equation below.

Whole body cooling(ΔT)=Heat removed/(mass*heat capacity)

Continuing the example above, for a 75 kg patient, the temperaturechange is calculated below to be 0.93° C. per hour, which is close tothe target cooling rate for patients.

$\begin{matrix}{{{Temperature}\mspace{14mu} {change}} = \frac{1000\mspace{14mu} {cal}\text{/}\min}{( {75,000\mspace{14mu} {grams}*0.85\mspace{14mu} {cal}\text{/}{gram}\mspace{14mu} {^\circ}\mspace{11mu} {C.}} }} \\{= {0.0157\mspace{11mu} {^\circ}\mspace{11mu} {C.\text{/}}\min}} \\{= {0.93\; {^\circ}\mspace{11mu} {C.\mspace{14mu} {per}}\mspace{14mu} {hour}}}\end{matrix}$

For whole body cooling (WBC), the following formula can be developedfrom the above:

WBC(° C./hr)=ΔT(liquid,° C.)*Flow rate(ml/min)/(Patient wt(kg)*14.3)

or

WBC(° C./hr)=Cooling(watts)/Patient Weight(kg)

The surface of the balloon may be treated or modified to maximizethermal conductance. A gel may also be optionally applied to theexterior of flexible balloons 204, 254 before insertion into the nasalcavity. The gel would preferably have good thermal conduction propertiesand be a better conductor than air. Additionally, the gel could also actas a lubricant to assist in the insertion. The gel may include, but isnot limited to, any aqueous gel, a poloxamer-based gel, a cellulose gel(such as KY jelly), a nasal-packing jelly, or a thermal gel.Alternatively, sponges may be attached to the surface of the balloon.Sponges, such as PVA sponges, are commonly used as packing material innoses and will conform to the shapes of the nasal cavity when wet.Alternatively, a hydrophilic coating may also be applied to the outersurface of the balloon to prevent beading on the outside.

Advantages of this apparatus and method include rapid circulation of thecooling fluid, rapid transfer of heat from the flexible balloon to themembranes of the nasal cavity, and flexibility in choice of coolantbecause the fluid is contained. Heat is transferred through the mucosafrom the pool of blood in the cavernous sinus to the cooling fluid inthe flexible balloon, thereby cooling the pool of blood in the cavernoussinus. Consequently, the blood in the carotid arteries, which runsthrough the cavernous sinus, is also cooled as it travels to the brain.In particular, the maximal heat exchange will likely be with theascending carotid arteries immediately before entry into theintracranial space and the terminal portion of the extracranial internalcarotid artery.

In another aspect of the invention, as seen in FIG. 49, thermoconductinggel 850 may be inserted into the nasal cavity of a patient tosubstantially fill the cavity. Cooling device 852, such as a cold probeor heat pipe, can then be directly inserted into gel 852 to cool gel852, thereby cooling the nasal cavity. The conductive device could be ametal, such as copper. Alternatively, conductive device 852 may be aprobe through which a chilled fluid is circulated, a probe in which afluid undergoes a phase change, or a heat pipe, which is a sealed systemutilizing an internal fluid that boils on one end and condenses on theother end in order to transmit heat. In the case of the probe with thefluid undergoing a phase change, the fluid may have a boiling pointbelow body temperature, such as a perfluorocarbon or Freon.Additionally, external cooling source 854, such as a refrigerationsystem, thermoelectric heat pump, ice bath, or evaporative cooler, willbe connected to the proximal end of the probe. Consequently, a cerebraltemperature of the patient can be reduced by at least 1° C. in one hour,alternatively at least 2° C. in one hour, at least 3° C. in one hour.

In another aspect of the invention, a sponge may be inserted into thenasal cavity of a patient to substantially fill the cavity. As mentionedpreviously, the sponge could surround the outside of a balloon to helpfill the nasal cavity. The sponges may help to fill the back of themouth and come into intimate contact with the soft palate and upperpharynx. Alternatively, the sponge could be inserted into the nasalcavity alone. The sponge could be connected to an inlet and outlettubular member to allow for circulation of fluids within the sponge. Incontrast to the balloon, the increased surface area of the sponge wouldallow for better contact with the interior surfaces of the nasal cavity.Additionally, the sponges could be designed with finger or hair-likeextrusions to increase the surface area, thereby increasing contact withthe interior surfaces of the nasal cavity. A hollow tube could beinserted through the sponge and/or balloon to facilitate breathing.

Convective Cooling in Other Parts of the Body

In another aspect of this invention, a modified nasogastric tube with aflexible balloon having a chamber filled with a cooling liquid may beused to cool the brain. As seen in FIG. 24, the assembly includesnasogastric tuber 356 having lumen 357, flexible balloon 354 that ismounted circumferentially around nasogastric tube 356 for the length ofthe esophagus, and elongate tubular member 360 having lumen 362.Nasogastric tube 356 is approximately 0.8 m in length, alternativelyapproximately 1 m in length, alternatively approximately 1.2 m inlength, alternatively approximately 1.4 m in length, alternativelyapproximately 1.6 m in length, alternatively approximately 1.8 m inlength, alternatively between about 0.8 m and 1.8 m in length. Anadditional flexible balloon 358 may be attached at the distal end of thenasogastric tube 356. Flexible balloon 358 would be in fluidcommunication with lumen 357 of nasogastric tube 356 and a chamber offlexible balloon 354 and, upon expansion, would be sized tosubstantially fill the patient's stomach. Alternatively, at its distalend, flexible balloon 354 may be sized and shaped to substantially fillthe patient's stomach upon expansion. At their proximal ends, elongatetubular member 360 and nasogastric tube 356 are connected to a pump anda cooler (not shown) or a refrigerated pump (not shown) that is capableof infusing and/or recycling a cooling fluid through flexible balloons354, 358. Flexible balloons 354, 358 are sized that upon inflation, theyare capable of making good contact with the surfaces of the adjacentanatomy, e.g., nasal cavity, esophagus, or stomach. Flexible balloons354, 358 are also preferably oversized and made of a soft, conformable,elastomeric material to provide maximum surface contact with the anatomyin which they are positioned. Flexible balloons 354, 358 may alsoinclude a check valve (not shown) that will release fluid, therebyreducing pressure of flexible balloons 354, 358 when they reach acertain pressure. Optionally, all or a portion of flexible balloons 354,358 may be made of a porous material that allows for the controlledrelease of drugs.

In use, the patient is intubated and the assembly is inserted through apatient's nostril, down the back of the throat, through the esophagus,and into the stomach. The assembly is positioned such that flexibleballoon 354 is located in the nasal cavity and the esophagus andflexible balloon 358 is located in the stomach. A cooling fluid can thenbe infused into flexible balloons 354, 358 to expand the balloons suchthat they substantially fill and contact the nasal cavity, esophagus,and stomach, respectively. The cooling fluid could be pumped in throughnasogastric tube 354 and suctioned out of elongate tubular member 360 ata rate sufficient to induce or maintain a desired pressure in theflexible balloons 354, 358 or a desired brain temperature. The coolingfluid may then be recirculated through flexible balloons 354, 358 vianasogastric tube 356, shaft 360, and a refrigerated pump (not shown).

In another aspect of this invention, a modified laryngeal mask having aflexible balloon having a chamber filled with a cooling liquid can beused to cool the brain. As seen in FIG. 25A, the laryngeal mask 320includes an elongate tubular member 322 having a proximal end, a distalend, and a lumen 323 therebetween that communicates with ports at theproximal and distal ends. The elongate tubular member 322 is preferablycurved to match the anatomy of the oropharynx. Toroidal balloon 324 hasa chamber, and surrounds port 325 at the distal end of elongate tubularmember 322, wherein the chamber is in fluid communication with lumens326, 328 of elongate tubular members 327, 329. Alternatively, lumens326, 328 may be part of elongate tubular member 322. Elongate tubularmembers 327, 329 are also connected to a pump and cooling unit (notshown) or a refrigerated pump (not shown) that is capable of infusingand/or recycling a cooling fluid through flexible toroidal balloon 324.The cooling fluid may include, but is not limited to, water, saline,PFC, anti-freeze solution, or a combination thereof. As seen in FIG.25B, the modified laryngeal mask may also include an additional balloon330 that is located on the distal region of the backside of elongatetubular member 322, wherein a chamber of additional balloon 330 is influid communication with lumens 332, 334. Lumens 332, 334 may be part ofelongate tubular member 322 or part of separate elongate tubularmembers. Additionally, the camber of additional balloon 330 mayalternatively be in fluid communication with lumens 326, 328 (notshown). Lumens 332, 334 would also be connected to a pump and coolingunit (not shown) or a refrigerated pump (not shown) that is capable ofrecycling the cooling fluid through flexible balloon 330.

In use, as seen in FIG. 25C, the modified laryngeal mask 320 ispositioned in the patient to sit tightly over the larynx. Toroidalballoon 324 is emptied before insertion and lubricated with a gel. Inaddition to being a good lubricant, the gel would also preferably havegood thermal conduction properties and be a better conductor than air.The gel may include, but is not limited to, a poloxomer-based gel (suchas KY jelly) or a packing jelly. The neck of the patient is extended andthe mouth is opened widely. The apex of the laryngeal mask 320, with theport or opening 325 pointing downwards toward the tongue, is pushedbackwards toward the uvula. Elongate tubular member 322 follows thenatural bend of the oropharynx and the mask comes to rest over thepuriform fossa. A cooling fluid can then be used to infuse and/orinflate toroidal balloon 324 to a sufficient pressure such that toroidalballoon 324 sits tightly over the larynx and is in contact with theepiglotis. The cooling fluid may then be recirculated through toroidalballoon 324 via lumens 326, 328, cooler (not shown), and pump (notshown). Additionally, the cooling fluid can be withdrawn or suctionedout of toroidal balloon 324 at a rate sufficient to induce or maintain adesired balloon pressure or brain temperature. During the coolingprocess, the airway is protected by the elongate tubular member 322.

In another aspect of this invention, a cooling pad may be used to coolthe brain via the oral cavity. As seen in FIG. 26, the assembly 400includes a flexible balloon or pad 402 having a chamber, tubular members403, 405 having lumens 404, 406 and ports 405, 407, wherein the chamberis in fluid communication with port 405, 407 and lumber 404, 406. Attheir proximal ends, tubular members 403, 405 are connected to cooler410 and pump 412. Alternatively, tubular members 403, 405 may beconnected to a refrigerated pump (not shown) that is capable of infusingand/or recirculating cooling fluid. The pad may be about 2.5 cm inlength, alternatively about 3 cm in length, alternatively about 3.5 cmin length.

In use, the assembly 400 is inserted into the oral cavity through themouth such that the flexible balloon or pad 402 covers theretromandibular area or peritonsillar region. A cooling fluid can thenbe infused into the chamber of flexible balloon or pad 402 to expand itto a sufficient pressure such that flexible balloon or pad 402 issubstantially in contact with the retromandibular area or peritonsillarregion. The cooling fluid may then be recirculated through flexibleballoon 402 via lumens 404, 406, using pump 412 and cooler 410 or arefrigerated pump. The cooling fluid can also be withdrawn or suctionedout of the flexible balloon 402 at a rate sufficient to induce ormaintain a desired balloon pressure or brain temperature. Cooling of thebrain may be achieved through convection or heat transfer betweenflexible balloon or pad 402 and the extracranial carotid artery.

The cooling fluid used with these inventions may include, but is notlimited to, water, saline, PFC, anti-freeze solution, or a combinationthereof. The temperature of the cooling fluid will preferably be belowbody temperature. The temperature of the cooling fluid may be betweenabout 37° C. to about −20° C., alternatively between about 30° C. toabout −20° C., alternatively between about 20° C. to about −20° C.,alternatively about 0° C., alternatively about 5° C., alternativelyabout −5° C., alternatively between about −5° C. to about 10° C.,alternatively between about −5° C. to about 5° C., alternatively betweenabout 0° C. to about 5° C. When saline is used as the cooling fluid, thesaline will preferably be about 0° C. The cooling fluid shouldrecirculate at a fast enough rate to maintain the low temperatureswithin the balloon. The flow rate of the cooling liquid by be betweenabout 5 and about 5 L/min, alternatively between about 100 and about 400ml/min, alternatively between about 200 and about 300 ml/min,alternatively between about 150 to about 200 ml/min.

Optionally, a gel may also be optionally applied to the exterior offlexible balloons before insertion into the oral cavity. The gel wouldpreferably have good thermal conduction properties and be a betterconductor than air. Additionally, the gel could also act as a lubricantto assist in the insertion. The gel may include, but is not limited to,any aqueous gel, a poloxamer-based gel, a cellulose gel (such as KYjelly), a nasal-packing jelly, or a thermal gel. Alternatively, spongesmay be attached to the surface of the balloon. Sponges, such as PVAsponges, are commonly used as packing material and will conform to theshapes of the oral cavity when wet. The sponges could be designed withfinger or hair-like extrusions to increase the surface area, therebyincreasing contact with the interior surfaces of the oral cavity. Thesponges may fill the back of the mouth and allow for maximal cooling atthe soft palate and retropharynx. Alternatively, a hydrophilic coatingmay also be applied to the outer surface of the balloon to preventbeading on the outside. A tube may also be inserted to allow breathing.

Fluid/Gas Delivery Systems

In another embodiment, the invention includes a liquid and gas deliverysystem for the delivery of a fixed, or substantially fixed, ratio ofliquid and gas. As seen in FIG. 31, in delivery system 500, gas flowmeter 505 can be set to deliver a set flow of gas to mixing hub ormanifold 510 through gas line 507. As gas is delivered to manifold 510,gas will also flow to bottle 520 through gas line 508. Gas lines 507 and508 may also comprise a single branched tube (not shown). As reservoiror bottle 520 becomes pressurized, liquid 525 in bottle 520 will flowthrough line 530 to manifold 510. The flow of the liquid will directlydepend on the pressure of the gas being delivered from flow meter505—i.e., higher gas pressure will result in a faster flow of liquid.Therefore, a fixed ratio of liquid and gas can be delivered to themanifold. As the flow rate of the gas is increased, a proportionalincrease in the liquid flow rate occurs, such that the ratio of liquidto gas being delivered to mixing manifold 510 is maintained withouthaving to independently adjust the flow of the liquid. Flow restrictors535 and 536 can be set to each allow a specific flow of liquid for aspecific pressure of gas. For example, flow restrictor 535 may allow ahigher flow rate than flow restrictor 536 for a specific pressure ofgas. Stopcock 532 can be connected to line 530. Stopcock 532 is used todirect flow either to restrictor 535 or 536 or can be used to stopliquid flow altogether. Filter 537 can also be placed in line 530 beforemixing manifold 510. An overpressure safety device 515 within gas flowmeter 505 can stop the flow of gas if a certain pressure is detected.Activation of the overpressure safety device 515 would switch valve 570to stop gas flow and vent gas lines 507 and 508. Therefore, the pressurein gas lines 507 and 508 and bottle 520 will all be reduced to zero.Therefore, the flow of liquid will also be stopped by the activation ofsafety device 515. The gas could be air, oxygen, or a combinationthereof. The liquid could include a perfluorocarbon such asperfluorohexane, perfluoropentane, or 2-methyl-perfluoropentane.

Mixing manifold 510 can be connected to catheters 540 and 545, eachcontaining multiple delivery ports 541 and 546 for delivery of the gasand liquid mixture to, for instance, the nasal cavity. Liquid can flowfrom line 530 into liquid lumens 572 and 574 of catheters 540 and 545through ports 560 and 562, respectively. Similarly, gas can flow fromline 507 into lumens 542 and 547 of catheters 540 and 545 through portsin the distal ends of the respective catheters. The gas and liquid canlater be mixed and delivered to the nasal cavity through the multipleports 541 and 546 as a nebulized spray, as described above. Pressure inthe nasal cavity can be measured through pressure lines 511 and 512,which are in communication with ports 565 and 566 located near thedistal ends of catheters 540 and 545 through pressure lumens 576 and 578and ports 561 and 563, respectively. Alternatively, a separate cathetercould be inserted to measure the pressure in the nasal cavity (notshown). If a pressure measured in the nasal cavity in which the liquidand gas is being delivered is found to be too high, overpressure safetydevice 515 will stop the flow of gas, and consequently, the flow ofliquid, to the nasal cavity. Additionally, the stopcock could be closedwhen it is desired to only deliver a gas, for instance, oxygen, ratherthan cool the patient.

An alternative embodiment of the liquid and gas delivery system isdepicted in FIG. 45. The mixing catheter may further include a liquiddelivery system for using the pressure from the compressed gas source todeliver the liquid to the nasal catheter. In this device, both the gasand the liquid are delivered strictly using the pressure from thecompressed gas source without the use of pumps or electronics. Here,inlet valve 964 is connected to compressed gas source 960, for example,oxygen or an oxygen and air mixture regulated to about 50 psi. Inletvalve 964 blocks or allows the pressurized gas into the rest of thesystem. When inlet valve 964 is in the “blocked” position, valve 964also may vent pressure from the system. Pressure regulator 962 may alsoallow better control of the gas pressure delivered to the liquiddelivery system and to the nasal catheter. When the inlet valve is inthe “allow” position, the gas flow splits in two directions, i.e., flowis connected to the gas flow channel 978 of the dual lumen tubing (notshown) and flow is also directed to fluid reservoir container 968 thatis designed to hold the desired dose of a liquid.

The fluid control reservoir 968 is rated to withstand the pressure ofthe compressed gas, for example the fluid control reservoir may be apoly ethylene teraphalate (PET) container tested to pressures in excessof 150 psi. In addition, a burst disk or relief valve 966, set at avalue exceeding the expected operating pressure, for example 60 psi,alternatively 70 psi, alternatively 80 psi, alternatively 90 psi, may beadded to the fluid reservoir container as a safety means for venting gasin the event of over pressurization. When the pressurized gas flows intofluid reservoir 968, the fluid is routed though an outlet port in thereservoir that is in fluid communication with liquid channel 980 of thedual lumen tubing (not shown). The outlet port may include fluid flowcontrolling device 972, such as a needle type valve or a variablediameter aperture, to adjust the flow rate of fluid into liquid channel980 of the dual lumen tubing. In addition, gas flow channel 978 of thedual lumen tubing may also include flow controlling device 970, such asa needle type valve or a variable diameter aperture, to adjust the flowrate of gas into the gas channel of the dual lumen tubing. The flowcontrol valves 970 and 972 of the gas and liquid channels may beindependently controlled by the operator to allow full flexibility invarying the gas and/or liquid flow to optimize the gas/liquid flowratio. The gas and liquid flow control valves 970 and 972 may have fixedorifices that produce a known constant flow for the gas and the liquid,or alternatively, the flow control valves 970 and 972 may include aselector (not shown) that would allow the operator to choose one ofseveral sets of orifices in order to provide the operator with a numberof choices for the flow, for example low flow, medium flow, high flow,induction, and maintenance flow rates. Here, each set point on theselector would use a predetermined orifice for the gas flow and amatched orifice for the liquid such that the gas/liquid flow rates andratios would be optimized for each condition. In an alternativeembodiment, the flow rate generated by the fixed orifices may be furtheraltered while maintaining the constant gas/liquid ration, by usingpressure regulator to regulate the input pressure of the gas source. Inaddition, liquid and gas flow meters 974 and 976 may be placed in theliquid and gas flow channels to further monitor and regulate the liquidand gas flow rates. Flow meters 974 and 976 may be any standard flowtechnology such as Turbines, paddlewheels, variable area Rota meters ormass flow meters. In addition, in-line filters (not shown) may be placedin both the gas and liquid channels to prevent particulate matter frombeing introduced to the patient.

Although the foregoing invention has, for the purposes of clarity andunderstanding, been described in some detail by way of illustration andexample, it will be obvious that certain changes and modifications maybe practiced which will still fall within the scope of the appendedclaims.

1. A method for cerebral cooling, comprising the steps of: inserting acooling assembly into an oral cavity of a patient through the patient'smouth, wherein the cooling assembly comprises: an elongate tubularmember having a proximal end, a distal end, first, second, and thirdlumens extending therebetween, openings in the distal and proximal endsin fluid communication with the first lumen, and at least one portlocated near the distal end in fluid communication with the secondlumen; an expandable member mounted circumferentially about the distalend of the elongate tubular member, the expandable member in fluidcommunication with the third lumen; advancing said cooling assembly insaid patient's oral cavity such that the expandable member is located inthe patient's trachea and the at least one port is located in thepatient's oral cavity; inflating the expandable member to form a sealsubstantially isolating the patient's oral cavities from the trachea;and delivering a perfluorocarbon to the patient's oral cavity throughthe at least one port in located in the patient's oral cavity.
 2. Themethod of claim 1, wherein the elongate tubular member further comprisesa second expandable member mounted on the proximal end.
 3. The method ofclaim 1, wherein the elongate tubular member further comprises a fourthlumen in fluid communication with a second port on the elongate tubularmember.
 4. The method of claim 1, wherein delivering a perfluorocarboncomprises delivering a perfluorocarbon spray and a gas through the atleast one port in located in the patient's oral cavity.
 5. The method ofclaim 4, wherein the gas is oxygen.
 6. The method of claim 1, whereinthe perfluorocarbon has a boiling point above 37° C.
 7. The method ofclaim 1, wherein the perfluorocarbon has a boiling point between about0° C. and about 160° C.
 8. The method of claim 1, wherein theperfluorocarbon has a boiling point between about 25° C. and about 140°C.
 9. The method of claim 1, wherein the perfluorocarbon isperfluorohexane.
 10. The method of claim 1, wherein the perfluorocarbon2-methyl perfluoropentane.
 11. The method of claim 1, wherein theperfluorocarbon spray is delivered at a temperature between about −5° C.and about 25° C.